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BACKGROUND: The integration of artificial intelligence (AI), particularly, in oncology, has significantly shifted the paradigms of medical diagnostics and treatment planning. However, the utility of AI, specifically OpenAI's ChatGPT, in soft tissue sarcoma treatment, remains unclear. METHODS: We evaluated ChatGPT's alignment with the Japanese Orthopaedic Association (JOA) clinical practice guidelines on the management of soft tissue tumors 2020. Twenty-two clinical questions (CQs) were formulated to encompass various aspects of sarcoma diagnosis, treatment, and management. ChatGPT's responses were classified into "Complete Alignment," "Partial Alignment," or "Nonalignment" based on the recommendation and strength of evidence. RESULTS: ChatGPT demonstrated an 86% alignment rate with the JOA guidelines. The AI provided two instances of complete alignment and 17 instances of partial alignment, indicating a strong capability to match guideline criteria for most questions. However, three discrepancies were identified in areas concerning the treatment of atypical lipomatous tumors, perioperative chemotherapy for synovial sarcoma, and treatment strategies for elderly patients with malignant soft tissue tumors. Reassessment with guideline input led to some adjustments, revealing both the potential and limitations of AI in complex sarcoma care. CONCLUSION: Our study demonstrates that AI, specifically ChatGPT, can align with clinical guidelines for soft tissue sarcoma treatment. It also underscores the need for continuous refinement and cautious integration of AI in medical decision-making, particularly in the context of treatment for soft tissue sarcoma.
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BACKGROUND: This study aims to evaluate the efficacy of radiation therapy in enhancing survival outcomes among elderly patients diagnosed with localized extremity soft tissue sarcomas (STSs). Furthermore, it seeks to explore whether the survival benefits conferred by radiation therapy differ according to tumor characteristics and treatment modalities. METHODS: We conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database to identify patients aged 80 years and older diagnosed with localized extremity STSs. The study assessed 1498 eligible patients, analyzing cancer-specific survival (CSS) and overall survival (OS) through Kaplan-Meier survival analysis and Cox proportional hazards modeling. Propensity score matching was employed to adjust for potential confounders. RESULTS: Among the analyzed patients, 773 patients underwent radiation therapy (Radiation group), while 725 patients either did not receive radiation therapy or it was unknown if they had (No-Radiation group). The 5-year OS rate was 40% in the radiation group compared to 38% in the no-radiation group. After propensity score matching, radiation therapy was associated with a significant improvement in OS (P = 0.005, HR = 0.8, 95% CI 0.7-0.9). Subgroup analyses indicated that patients undergoing primary tumor resection benefited most from radiation therapy in terms of OS. CONCLUSION: Radiation therapy is associated with improved overall survival in elderly patients with localized extremity STSs. These findings suggest that radiation therapy should be considered as a key component of the treatment strategy for this patient population, taking into account individual patient characteristics and comorbidities.
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INTRODUCTION: Growth plate damage in long bones often results in progressive skeletal growth imbalance and deformity, leading to significant physical problems. Gangliosides, key glycosphingolipids in cartilage, are notably abundant in articular cartilage and regulate chondrocyte homeostasis. This suggests their significant roles in regulating growth plate cartilage repair. METHODS: Chondrocytes from 3 to 5 day-old C57BL/6 mice underwent glycoblotting and mass spectrometry. Based on the results of the glycoblotting analysis, we employed GD3 synthase knockout mice (GD3-/-), which lack b-series gangliosides. In 3-week-old mice, physeal injuries were induced in the left tibiae, with right tibiae sham operated. Tibiae were analyzed at 5 weeks postoperatively for length and micro-CT for growth plate height and bone volume at injury sites. Tibial shortening ratio and bone mineral density were measured by micro-CT. RESULTS: Glycoblotting analysis indicated that b-series gangliosides were the most prevalent in physeal chondrocytes among ganglioside series. At 3 weeks, GD3-/- exhibited reduced tibial shortening (14.7 ± 0.2 mm) compared to WT (15.0 ± 0.1 mm, P = 0.03). By 5 weeks, the tibial lengths in GD3-/- (16.0 ± 0.4 mm) closely aligned with sham-operated lengths (P = 0.70). Micro-CT showed delayed physeal bridge formation in GD3-/-, with bone volume measuring 168.9 ± 5.8 HU at 3 weeks (WT: 180.2 ± 3.2 HU, P = 0.09), but normalizing by 5 weeks. CONCLUSION: This study highlights that GD3 synthase knockout mice inhibit physeal bridge formation after growth plate injury, proposing a new non-invasive approach for treating skeletal growth disorders.
Subject(s)
Chondrocytes , Gangliosides , Growth Plate , Mice, Inbred C57BL , Mice, Knockout , Animals , Growth Plate/pathology , Growth Plate/metabolism , Gangliosides/metabolism , Chondrocytes/metabolism , Mice , Leg Length Inequality , Tibia/diagnostic imaging , Tibia/pathology , Tibia/metabolism , Tibia/growth & development , X-Ray Microtomography , Sialyltransferases/deficiency , Sialyltransferases/genetics , Sialyltransferases/metabolism , Disease Models, AnimalABSTRACT
BACKGROUND: The study examines the characteristics and outcomes of foot-originating malignant bone tumors via Surveillance Epidemiology and End Results (SEER) database analysis. METHODS: A retrospective review of 14,695 malignant bone tumor cases from 2000 to 2019 was conducted. RESULTS: Of the eligible cases, 147 (2.3 %) were foot-origin tumors, typically smaller and more commonly treated with surgery than those in other locations. These tumors were more frequently treated with surgical resection, with a higher proportion undergoing amputation. In contrast, foot-origin tumors were less often managed with chemotherapy and radiation. Foot-origin tumors exhibited higher survival rates compared to non-foot-origin tumors as shown in univariate analysis, although multivariate analysis did not reflect significant differences. CONCLUSION: Foot-originating malignant bone tumors tend to be smaller and are frequently surgically treated, correlating with favorable survival outcomes. These findings point to early detection as a potential factor in the improved survival rates, not necessarily the tumor's origin.
ABSTRACT
Osteoid osteomas are benign, typically intracortical lesions most often affecting the diaphysis of long bones. Nocturnal pain and characteristic symptoms that are relieved by administration of non-steroidal anti-inflammatory drugs (NSAIDs) are present and can help in the diagnosis of osteoid osteoma. We report a case of 18-year-old boy with an osteoid osteoma in the olecranon fossa with an atypical clinical manifestation. The initial manifestation was arthritis-like symptoms such as local heat, motion pain rather than pain at rest, and limited range-of-motion. Notably, NSAIDs were not effective at all for relieving his symptoms. Magnetic resonance imaging showed bone marrow edema around the elbow joint. The symptoms were resistant to conservative treatments, and thus, surgical resection was required. Histopathological examination showed that the lesion consisted of woven bones and osteoid tissues that anastomosed with each other. Combined with a tumor size that was less than 2 cm, clinicopathologically, the tumor was diagnosed as an osteoid osteoma. The pain was immediately relieved after the operation, and range-of-motion recovered at 2 months postoperatively. At 1 year after the surgery, the patient did not exhibit recurrence of the tumor or exacerbation of elbow pain and had a full range of elbow motion. Osteoid osteoma should be considered for the differential diagnosis of arthritis of the elbow in patients who are adolescents and young adults, which is the peak age of onset for osteoid osteoma.
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BACKGROUND: Hemarthrosis after total knee arthroplasty (TKA) is a relatively rare complication. Although most cases are effectively treated with conservative therapy, some cases require angiographic embolization or surgical intervention. Angiosarcoma is a rare malignant tumor derived from the vascular endothelium with neovascular hyperplasia and mainly arises in the skin and superficial soft tissue, and less frequently in deep soft tissue and bone. Although malignant neoplasms such as angiosarcoma in the vicinity of orthopedic implants were reported, the causal relationship between development of the malignant tumor and the orthopedic implant is widely debated in the literature. CASE PRESENTATION: We report the case of a 68-year-old female with angiosarcoma that developed in the knee joint 2 years after revision TKA. The patient exhibited severe persistent bleeding, which reached 1000-1400 ml per day for 4 months. Histological analysis of the synovial tissue in the knee joint showed large cells with nuclear atypia. Immunohistochemical staining showed cells that were positive for CD31, CD34, and D2-40, and she was diagnosed with angiosarcoma. The patient underwent an amputation at the level of the thigh, and her general condition immediately improved after the operation. The patient did not exhibit bleeding from the site of amputation, and no local recurrence or distant metastases were detected 1 year after the amputation. CONCLUSIONS: To the best of our knowledge, this represents the first report of angiosarcoma 2 years after revision TKA. Further careful follow up is needed, given the high-grade malignancy.
Subject(s)
Arthroplasty, Replacement, Knee/adverse effects , Bone Neoplasms/etiology , Hemangiosarcoma/etiology , Knee Joint/surgery , Postoperative Complications , Bone Neoplasms/diagnosis , Female , Hemangiosarcoma/diagnosis , Humans , Knee Joint/diagnostic imaging , Middle Aged , ReoperationABSTRACT
Cardiac metabolism plays a crucial role in producing sufficient energy to sustain cardiac function. However, the role of metabolism in different aspects of cardiomyocyte regeneration remains unclear. Working with the adult zebrafish heart regeneration model, we first find an increase in the levels of mRNAs encoding enzymes regulating glucose and pyruvate metabolism, including pyruvate kinase M1/2 (Pkm) and pyruvate dehydrogenase kinases (Pdks), especially in tissues bordering the damaged area. We further find that impaired glycolysis decreases the number of proliferating cardiomyocytes following injury. These observations are supported by analyses using loss-of-function models for the metabolic regulators Pkma2 and peroxisome proliferator-activated receptor gamma coactivator 1 alpha. Cardiomyocyte-specific loss- and gain-of-function manipulations of pyruvate metabolism using Pdk3 as well as a catalytic subunit of the pyruvate dehydrogenase complex (PDC) reveal its importance in cardiomyocyte dedifferentiation and proliferation after injury. Furthermore, we find that PDK activity can modulate cell cycle progression and protrusive activity in mammalian cardiomyocytes in culture. Our findings reveal new roles for cardiac metabolism and the PDK-PDC axis in cardiomyocyte behavior following cardiac injury.
Subject(s)
Myocytes, Cardiac , Zebrafish , Animals , Cell Proliferation , Glycolysis , Myocytes, Cardiac/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Zebrafish/metabolismABSTRACT
To dissect the TBX5 regulatory circuit, we focused on microRNAs (miRNAs) that collectively contribute to make TBX5 a pivotal cardiac regulator. We profiled miRNAs in hearts isolated from wild-type, CRE, Tbx5lox/+and Tbx5del/+ mice using a Next Generation Sequencing (NGS) approach. TBX5 deficiency in cardiomyocytes increased the expression of the miR-183 cluster family that is controlled by Kruppel-like factor 4, a transcription factor repressed by TBX5. MiR-182-5p, the most highly expressed miRNA of this family, was functionally analyzed in zebrafish. Transient overexpression of miR-182-5p affected heart morphology, calcium handling and the onset of arrhythmias as detected by ECG tracings. Accordingly, several calcium channel proteins identified as putative miR-182-5p targets were downregulated in miR-182-5p overexpressing hearts. In stable zebrafish transgenic lines, we demonstrated that selective miRNA-182-5p upregulation contributes to arrhythmias. Moreover, cardiac-specific down-regulation of miR-182-5p rescued cardiac defects in a zebrafish model of Holt-Oram syndrome. In conclusion, miR-182-5p exerts an evolutionarily conserved role as a TBX5 effector in the onset of cardiac propensity for arrhythmia, and constitutes a relevant target for mediating the relationship between TBX5, arrhythmia and heart development.
Subject(s)
Heart/growth & development , MicroRNAs/genetics , T-Box Domain Proteins/genetics , Zebrafish/genetics , Animals , Animals, Genetically Modified/genetics , Animals, Genetically Modified/metabolism , Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/metabolism , Calcium/metabolism , Cell Line , Down-Regulation/genetics , Female , Gene Expression Regulation/genetics , Kruppel-Like Factor 4 , Mice , Mice, Inbred C57BL , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/physiology , Pregnancy , T-Box Domain Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Up-Regulation/genetics , Zebrafish/metabolismABSTRACT
During cardiac development, cardiomyocytes form complex inner wall structures called trabeculae. Despite significant investigation into this process, the potential role of metabolism has not been addressed. Using single cell resolution imaging in zebrafish, we find that cardiomyocytes seeding the trabecular layer actively change their shape while compact layer cardiomyocytes remain static. We show that Erbb2 signaling, which is required for trabeculation, activates glycolysis to support changes in cardiomyocyte shape and behavior. Pharmacological inhibition of glycolysis impairs cardiac trabeculation, and cardiomyocyte-specific loss- and gain-of-function manipulations of glycolysis decrease and increase trabeculation, respectively. In addition, loss of the glycolytic enzyme pyruvate kinase M2 impairs trabeculation. Experiments with rat neonatal cardiomyocytes in culture further support these observations. Our findings reveal new roles for glycolysis in regulating cardiomyocyte behavior during cardiac wall morphogenesis.
Subject(s)
Heart/embryology , Heart/growth & development , Morphogenesis/physiology , Myocytes, Cardiac/metabolism , Zebrafish/embryology , Zebrafish/growth & development , Zebrafish/metabolism , Animals , Animals, Genetically Modified , Cell Proliferation , Gene Expression Regulation, Developmental , Genes, erbB-2/genetics , Glycolysis , Heart/physiology , Models, Animal , Morphogenesis/genetics , Organogenesis/genetics , Organogenesis/physiology , Rats , Signal Transduction/physiology , Zebrafish/genetics , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolismABSTRACT
Mechanical forces regulate cell behavior and tissue morphogenesis. During cardiac development, mechanical stimuli from the heartbeat are required for cardiomyocyte maturation, but the underlying molecular mechanisms remain unclear. Here, we first show that the forces of the contracting heart regulate the localization and activation of the cytoskeletal protein vinculin (VCL), which we find to be essential for myofilament maturation. To further analyze the role of VCL in this process, we examined its interactome in contracting versus non-contracting cardiomyocytes and, in addition to several known interactors, including actin regulators, identified the slingshot protein phosphatase SSH1. We show how VCL recruits SSH1 and its effector, the actin depolymerizing factor cofilin (CFL), to regulate F-actin rearrangement and promote cardiomyocyte myofilament maturation. Overall, our results reveal that mechanical forces generated by cardiac contractility regulate cardiomyocyte maturation through the VCL-SSH1-CFL axis, providing further insight into how mechanical forces are transmitted intracellularly to regulate myofilament maturation.
Subject(s)
Cofilin 1/metabolism , Heart/embryology , Myocytes, Cardiac/metabolism , Phosphoprotein Phosphatases/metabolism , Vinculin/metabolism , Actin Cytoskeleton/metabolism , Actin Depolymerizing Factors/metabolism , Actins/metabolism , Aminobenzoates/pharmacology , Animals , Gene Expression Regulation, Developmental , Microfilament Proteins/metabolism , Myocardium/metabolism , Myofibrils/metabolism , Sodium-Calcium Exchanger/metabolism , ZebrafishABSTRACT
Genetic robustness, or the ability of an organism to maintain fitness in the presence of harmful mutations, can be achieved via protein feedback loops. Previous work has suggested that organisms may also respond to mutations by transcriptional adaptation, a process by which related gene(s) are upregulated independently of protein feedback loops. However, the prevalence of transcriptional adaptation and its underlying molecular mechanisms are unknown. Here, by analysing several models of transcriptional adaptation in zebrafish and mouse, we uncover a requirement for mutant mRNA degradation. Alleles that fail to transcribe the mutated gene do not exhibit transcriptional adaptation, and these alleles give rise to more severe phenotypes than alleles displaying mutant mRNA decay. Transcriptome analysis in alleles displaying mutant mRNA decay reveals the upregulation of a substantial proportion of the genes that exhibit sequence similarity with the mutated gene's mRNA, suggesting a sequence-dependent mechanism. These findings have implications for our understanding of disease-causing mutations, and will help in the design of mutant alleles with minimal transcriptional adaptation-derived compensation.
Subject(s)
Adaptation, Physiological/genetics , Mutation , RNA Stability/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription, Genetic/genetics , Up-Regulation/genetics , Alleles , Animals , Epigenesis, Genetic/genetics , Histones/metabolism , Mice , Zebrafish/geneticsABSTRACT
Elucidating the morphogenetic events that shape vertebrate heart valves, complex structures that prevent retrograde blood flow, is critical to understanding valvular development and aberrations. Here, we used the zebrafish atrioventricular (AV) valve to investigate these events in real time and at single-cell resolution. We report the initial events of collective migration of AV endocardial cells (ECs) into the extracellular matrix (ECM), and their subsequent rearrangements to form the leaflets. We functionally characterize integrin-based focal adhesions (FAs), critical mediators of cell-ECM interactions, during valve morphogenesis. Using transgenes to block FA signaling specifically in AV ECs as well as loss-of-function approaches, we show that FA signaling mediated by Integrin α5ß1 and Talin1 promotes AV EC migration and overall shaping of the valve leaflets. Altogether, our investigation reveals the critical processes driving cardiac valve morphogenesis in vivo and establishes the zebrafish AV valve as a vertebrate model to study FA-regulated tissue morphogenesis.
Subject(s)
Endocardium/embryology , Focal Adhesions/metabolism , Heart Valves/embryology , Organogenesis , Signal Transduction , Zebrafish/embryology , Animals , Cell Movement , Extracellular Matrix/genetics , Extracellular Matrix/metabolism , Focal Adhesions/genetics , Integrin alpha5beta1/genetics , Integrin alpha5beta1/metabolism , Talin/genetics , Talin/metabolism , Zebrafish/genetics , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolismABSTRACT
Tissue integrity is critical for organ formation and function. During heart development, cardiomyocytes differentiate and integrate to form a coherent tissue that contracts synchronously. However, the molecular mechanisms regulating cardiac tissue integrity are poorly understood. Here we show that proteolysis, via the E3 ubiquitin ligase ASB2, regulates cardiomyocyte maturation and tissue integrity. Cardiomyocytes in asb2b zebrafish mutants fail to terminally differentiate, resulting in reduced cardiac contractility and output. Mosaic analyses reveal a cell-autonomous requirement for Asb2b in cardiomyocytes for their integration as asb2b mutant cardiomyocytes are unable to meld into wild-type myocardial tissue. In vitro and in vivo data indicate that ASB2 negatively regulates TCF3, a bHLH transcription factor. TCF3 must be degraded for cardiomyocyte maturation, as TCF3 gain-of-function causes a number of phenotypes associated with cardiomyocyte dedifferentiation. Overall, our results show that proteolysis has an important role in cardiomyocyte maturation and the formation of a coherent myocardial tissue.
Subject(s)
Myocytes, Cardiac/metabolism , Organogenesis , Proteolysis , Zebrafish/growth & development , Zebrafish/metabolism , Animals , Animals, Newborn , Base Sequence , Cell Dedifferentiation , Heart Defects, Congenital/metabolism , Heart Defects, Congenital/pathology , Mice , Mutation/genetics , Myocytes, Cardiac/pathology , Rats , Zebrafish/geneticsABSTRACT
During cardiac trabeculation, cardiomyocytes delaminate from the outermost (compact) layer to form complex muscular structures known as trabeculae. As these cardiomyocytes delaminate, the remodeling of adhesion junctions must be tightly coordinated so cells can extrude from the compact layer while remaining in tight contact with their neighbors. In this study, we examined the distribution of N-cadherin (Cdh2) during cardiac trabeculation in zebrafish. By analyzing the localization of a Cdh2-EGFP fusion protein expressed under the control of the zebrafish cdh2 promoter, we initially observed Cdh2-EGFP expression along the lateral sides of embryonic cardiomyocytes, in an evenly distributed pattern, and with the occasional appearance of punctae. Within a few hours, Cdh2-EGFP distribution on the lateral sides of cardiomyocytes evolves into a clear punctate pattern as Cdh2-EGFP molecules outside the punctae cluster to increase the size of these aggregates. In addition, Cdh2-EGFP molecules also appear on the basal side of cardiomyocytes that remain in the compact layer. Delaminating cardiomyocytes accumulate Cdh2-EGFP on the surface facing the basal side of compact layer cardiomyocytes, thereby allowing tight adhesion between these layers. Importantly, we find that blood flow/cardiac contractility is required for the transition from an even distribution of Cdh2-EGFP to the formation of punctae. Furthermore, using time-lapse imaging of beating hearts in conjunction with a Cdh2 tandem fluorescent protein timer transgenic line, we observed that Cdh2-EGFP molecules appear to move from the lateral to the basal side of cardiomyocytes along the cell membrane, and that Erb-b2 receptor tyrosine kinase 2 (Erbb2) function is required for this relocalization.
Subject(s)
Cadherins/metabolism , Heart/embryology , Myocytes, Cardiac/metabolism , Zebrafish Proteins/metabolism , Animals , Animals, Genetically Modified , Coronary Circulation , Green Fluorescent Proteins , Myocardial Contraction , Receptor, ErbB-2/metabolism , ZebrafishABSTRACT
BACKGROUND: We have developed genetic methods in zebrafish by using the Tol2 transposable element; namely, transgenesis, gene trapping, enhancer trapping and the Gal4FF-UAS system. Gene trap constructs contain a splice acceptor and the GFP or Gal4FF (a modified version of the yeast Gal4 transcription activator) gene, and enhancer trap constructs contain the zebrafish hsp70l promoter and the GFP or Gal4FF gene. By performing genetic screens using these constructs, we have generated transgenic zebrafish that express GFP and Gal4FF in specific cells, tissues and organs. Gal4FF expression is visualized by creating double transgenic fish carrying a Gal4FF transgene and the GFP reporter gene placed downstream of the Gal4-recognition sequence (UAS). Further, the Gal4FF-expressing cells can be manipulated by mating with UAS effector fish. For instance, when fish expressing Gal4FF in specific neurons are crossed with the UAS:TeTxLC fish carrying the tetanus neurotoxin gene downstream of UAS, the neuronal activities are inhibited in the double transgenic fish. Thus, these transgenic fish are useful to study developmental biology and neurobiology. DESCRIPTION: To increase the usefulness of the transgenic fish resource, we developed a web-based database named zTrap http://kawakami.lab.nig.ac.jp/ztrap/. The zTrap database contains images of GFP and Gal4FF expression patterns, and genomic DNA sequences surrounding the integration sites of the gene trap and enhancer trap constructs. The integration sites are mapped onto the Ensembl zebrafish genome by in-house Blat analysis and can be viewed on the zTrap and Ensembl genome browsers. Furthermore, zTrap is equipped with the functionality to search these data for expression patterns and genomic loci of interest. zTrap contains the information about transgenic fish including UAS reporter and effector fish. CONCLUSION: zTrap is a useful resource to find gene trap and enhancer trap fish lines that express GFP and Gal4FF in desired patterns, and to find insertions of the gene trap and enhancer trap constructs that are located within or near genes of interest. These transgenic fish can be utilized to observe specific cell types during embryogenesis, to manipulate their functions, and to discover novel genes and cis-regulatory elements. Therefore, zTrap should facilitate studies on genomics, developmental biology and neurobiology utilizing the transgenic zebrafish resource.
Subject(s)
Animals, Genetically Modified/genetics , Databases, Genetic , Enhancer Elements, Genetic , Zebrafish/genetics , Animals , DNA Transposable Elements/genetics , Gene Expression Regulation, Developmental , Genes, Reporter , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Software , Transgenes , Zebrafish/embryology , Zebrafish/growth & developmentABSTRACT
Each dental adhesive contains a specific functional monomer that determines its actual adhesive performance to tooth tissue. 4-methacryloxyethyl trimellitic acid (4-MET) is well-known as one of the functional monomers mostly available and consequently widely used in commercial adhesives. We therefore characterized the chemical interaction of 4-MET with hydroxyapatite (HAp) using X-ray Photoelectron Spectroscopy (XPS). XPS revealed that the peak representing -COO- of 4-MET shifted to a lower binding energy, when 4-MET was adsorbed onto HAp. Deconvolution of this shifted peak disclosed two components with a peak representing unreacted carboxyl groups and ester groups, and a peak suggesting chemical bonding of other carboxyl groups to Ca of HAp. XPS spectra of HAp treated with 4-MET also disclosed the surface to be enriched in calcium and decreased in phosphorus, indicating that phosphorus was extracted at a relatively higher rate than calcium. It can thus be concluded that true chemical bonding of 4-MET with calcium present in HAp occurred, as it was proven using XPS.
Subject(s)
Dental Bonding , Durapatite/chemistry , Methacrylates/chemistry , Resin Cements/chemistry , Tricarboxylic Acids/chemistry , Calcium/chemistry , Carbon Dioxide/chemistry , Phosphorus/chemistry , Spectrometry, X-Ray EmissionABSTRACT
Adult T cell leukemia/lymphoma (ATLL) has been characterized as one of the most aggressive human neoplasias and its incidence is thought to be caused by both genetic and epigenetic alterations to the host cellular genes of T cells infected with human T cell leukemia virus type I (HTLV-I). A multilobulated nuclear appearance is an important diagnostic marker of ATLL, and we have now identified that the molecular mechanisms underlying these formations occur through microtubule rearrangement via phosphatidylinositol 3-kinase (PI3-kinase) activation by AILIM/ICOS signaling. We also show that PTEN and/or SHIP-1, which are PIP3 inositol phosphatases that inhibit the activation of downstream effectors of the PI3-kinase cascade, are disrupted in both ATLL neoplasias and in multilobulated nuclei-forming Jurkat cells. This down-regulation of PTEN was found to be essential for the formation of ATLL-type nuclear lobules. Furthermore, PI3-kinase and PTEN activities were observed to be closely associated with cellular proliferation. Thus, our results suggest that alteration of PI3-kinase signaling cascades, as a result of the down-regulation of inositol phosphatases, induces ATLL-type multilobulated nuclear formation and is also associated with the cellular proliferation of malignant T cell leukemias/lymphomas.