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Life Science Alliance Aug 2024Dynamic rearrangements of the F-actin cytoskeleton are a hallmark of tumor metastasis. Thus, proteins that govern F-actin rearrangements are of major interest for...
Dynamic rearrangements of the F-actin cytoskeleton are a hallmark of tumor metastasis. Thus, proteins that govern F-actin rearrangements are of major interest for understanding metastasis and potential therapies. We hypothesized that the unique F-actin binding and bundling protein SWAP-70 contributes importantly to metastasis. Orthotopic, ectopic, and short-term tail vein injection mouse breast and lung cancer models revealed a strong positive dependence of lung and bone metastasis on SWAP-70. Breast cancer cell growth, migration, adhesion, and invasion assays revealed SWAP-70's key role in these metastasis-related cell features and the requirement for SWAP-70 to bind F-actin. Biophysical experiments showed that tumor cell stiffness and deformability are negatively modulated by SWAP-70. Together, we present a hitherto undescribed, unique F-actin modulator as an important contributor to tumor metastasis.
Topics: Animals; Actins; Mice; Humans; Female; Cell Line, Tumor; Neoplasm Metastasis; Breast Neoplasms; Lung Neoplasms; Microfilament Proteins; Cell Movement; Actin Cytoskeleton; Cell Proliferation; Cell Adhesion; Protein Binding
PubMed: 38760173
DOI: 10.26508/lsa.202302307 -
Medicine May 2024To explore the therapeutic mechanism of Mori Cortex against osteosarcoma (OS), we conducted bioinformatics prediction followed by in vitro experimental validation.
OBJECTIVE
To explore the therapeutic mechanism of Mori Cortex against osteosarcoma (OS), we conducted bioinformatics prediction followed by in vitro experimental validation.
METHODS
Gene expression data from normal and OS tissues were obtained from the GEO database and underwent differential analysis. Active Mori Cortex components and target genes were extracted from the Traditional Chinese Medicine System Pharmacology database. By intersecting these targets with differentially expressed genes in OS, we identified potential drug action targets. Using the STRING database, a protein-protein interaction network was constructed. Subsequent analyses of these intersected genes, including Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment, were performed using R software to elucidate biological processes, molecular functions, and cellular components, resulting in the simulation of signaling pathways. Molecular docking assessed the binding capacity of small molecules to signaling pathway targets. In vitro validations were conducted on U-2 OS cells. The CCK8 assay was used to determine drug-induced cytotoxicity in OS cells, and Western Blotting was employed to validate the expression of AKT, extracellular signal-regulated kinases (ERK), Survivin, and Cyclin D1 proteins.
RESULTS
Through differential gene expression analysis between normal and OS tissues, we identified 12,364 differentially expressed genes. From the TCSMP database, 39 active components and 185 therapeutic targets related to OS were derived. The protein-protein interaction network indicated that AKT1, IL-6, JUN, VEGFA, and CASP3 might be central targets of Mori Cortex for OS. Molecular docking revealed that the active compound Morusin in Mori Cortex exhibits strong binding affinity to AKT and ERK. The CCK8 assay showed that Morusin significantly inhibits the viability of U-2 OS cells. Western Blot demonstrated a reduction in the p-AKT/AKT ratio, the p-ERK/ERK ratio, Survivin, and Cyclin D1.
CONCLUSION
Mori Cortex may exert its therapeutic effects on OS through multiple cellular signaling pathways. Morusin, the active component of Mori Cortex, can inhibit cell cycle regulation and promote cell death in OS cells by targeting AKT/ERK pathway.
Topics: Osteosarcoma; Humans; Computational Biology; Molecular Docking Simulation; Cell Line, Tumor; Drugs, Chinese Herbal; Morus; Bone Neoplasms; Protein Interaction Maps; Signal Transduction; Gene Expression Regulation, Neoplastic; Medicine, Chinese Traditional; Survivin; Cyclin D1
PubMed: 38758844
DOI: 10.1097/MD.0000000000038261 -
Frontiers in Immunology 2024Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small-cell lung cancer (NSCLC), which is resistant to chemotherapy and radiotherapy with a poor prognosis....
BACKGROUND
Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small-cell lung cancer (NSCLC), which is resistant to chemotherapy and radiotherapy with a poor prognosis. PSC is highly malignant and is prone to recurrence even after surgery. The programmed death-ligand 1 (PD-L1) tumor cell proportion score (TPS) 5%, TERT and TP53 gene mutations were detected in this patient accompanied by multiple metastatic sites. The anlotinib is a novel multitarget tyrosine kinase inhibitor (TKI) that could be effective for advanced NSCLC and some sarcoma patients. Limited clinical trials and case reports have shown that PSC patients with gene mutations and PD-L1 expression have good responses to multitarget antiangiogenic drug and immune checkpoint inhibitors (ICIs). In this article, we reported a case with metastatic PSC diagnosed by Computed Tomography (CT)-guided needle biopsy treated with immunotherapy combined with antiangiogenic drugs as a neoadjuvant chemotherapy (NACT). PSC is controlled and the patient achieves successfully limb salvage treatment by surgical resection. Therefore, targeted therapy and immunotherapy can provide sufficient surgical opportunities for limb salvage in the treatment of metastatic PSC patients.
CASE SUMMARY
A 69-year-old male diagnosed with malignant bone tumor in the proximal femur was admitted to our hospital in June 2022 with recurrent fever as well as swelling and pain in the left thigh for twenty days. The initial computed tomography (CT) scan of the chest showed a pulmonary cavity (20 mm × 30 mm) and scattered lung masses. Subsequently, he underwent a CT-guided needle biopsy to distinguish the essence of osteolytic bone destruction and soft tissue mass in the left proximal femur which showed metastatic sarcomatoid carcinoma histology. Genetic testing revealed TERT c.-124C mutation (abundance 8.81%), TP53 p.R342 mutation (abundance 11.35%), tumor mutational burden (TMB) 7.09 muts/Mb, microsatellite stability (MSS), and PD-L1 (SP263) TPS 5% were also detected. The patient was tentatively treated with a combination of antiangiogenic drug and PD-1 inhibitor. After one course, the tumor volume significantly reduced in magnetic resonance imaging (MRI) and pathological fracture occurred in the femur after combined treatment. The patient received proximal femoral tumor resection and prosthesis replacement after defervescence. Sequentially sintilimab with anlotinib were administered for over 1 year. Finally, the local tumor was well controlled, and no obvious drug-related adverse reactions were observed. The lesions in the lung remained in partial response (PR) for more than 16 months and complete response (CR) of metastatic tumor in the proximal femur was observed through imaging examinations.
CONCLUSION
This is the first reported case of a metastatic PSC in femur showing a favorable response to the treatment consisting of anlotinib combined with sintilimab. This case suggests that antiangiogenic therapy combined with immunotherapy may benefit patients with metastatic PSC in the preoperative adjuvant therapy for limb salvage.
Topics: Humans; Antibodies, Monoclonal, Humanized; Bone Neoplasms; Lung Neoplasms; Quinolines; Neoadjuvant Therapy; Male; Indoles; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Aged; Treatment Outcome; Immune Checkpoint Inhibitors
PubMed: 38756778
DOI: 10.3389/fimmu.2024.1372279 -
BMC Medicine May 2024Osteosarcoma (OS) is the most common primary malignant bone tumor and is highly prone to metastasis. OS can metastasize to the lymph node (LN) through the lymphatics,...
BACKGROUND
Osteosarcoma (OS) is the most common primary malignant bone tumor and is highly prone to metastasis. OS can metastasize to the lymph node (LN) through the lymphatics, and the metastasis of tumor cells reestablishes the immune landscape of the LN, which is conducive to the growth of tumor cells. However, the mechanism of LN metastasis of osteosarcoma and remodeling of the metastatic lymph node (MLN) microenvironment is not clear.
METHODS
Single-cell RNA sequencing of 18 samples from paracancerous, primary tumor, and lymph nodes was performed. Then, new signaling axes closely related to metastasis were identified using bioinformatics, in vitro experiments, and immunohistochemistry. The mechanism of remodeling of the LN microenvironment in tumor cells was investigated by integrating single-cell and spatial transcriptomics.
RESULTS
From 18 single-cell sequencing samples, we obtained 117,964 cells. The pseudotime analysis revealed that osteoblast(OB) cells may follow a differentiation path from paracancerous tissue (PC) → primary tumor (PT) → MLN or from PC → PT, during the process of LN metastasis. Next, in combination of bioinformatics, in vitro and in vivo experiments, and immunohistochemistry, we determined that ETS2/IBSP, a new signal axis, might promote LN metastasis. Finally, single-cell and spatial dissection uncovered that OS cells could reshape the microenvironment of LN by interacting with various cell components, such as myeloid, cancer-associated fibroblasts (CAFs), and NK/T cells.
CONCLUSIONS
Collectively, our research revealed a new molecular mechanism of LN metastasis and clarified how OS cells influenced the LN microenvironment, which might provide new insight for blocking LN metastasis.
Topics: Osteosarcoma; Tumor Microenvironment; Humans; Single-Cell Analysis; Bone Neoplasms; Lymph Nodes; Lymphatic Metastasis; Transcriptome; Animals; Mice; Cell Line, Tumor; Gene Expression Profiling
PubMed: 38755647
DOI: 10.1186/s12916-024-03319-w -
BMC Musculoskeletal Disorders May 2024Customized 3D-printed pelvic implants with a porous structure have revolutionized periacetabular pelvic defect reconstruction after tumor resection, offering improved...
BACKGROUND
Customized 3D-printed pelvic implants with a porous structure have revolutionized periacetabular pelvic defect reconstruction after tumor resection, offering improved osteointegration, long-term stability, and anatomical fit. However, the lack of an established classification system hampers implementation and progress.
METHODS
We formulated a novel classification system based on pelvic defect morphology and 3D-printed hemipelvis endoprostheses. It integrates surgical approach, osteotomy guide plate and prosthesis design, postoperative rehabilitation plans, and perioperative processes.
RESULTS
Retrospectively analyzing 60 patients (31 males, 29 females), we classified them into Type A (15 patients: Aa = 6, Ab = 9), Type B (27 patients: Ba = 15, Bb = 12), Type C (17 patients). All underwent customized osteotomy guide plate-assisted tumor resection and 3D-printed hemipelvic endoprosthesis reconstruction. Follow-up duration was median 36.5 ± 15.0 months (range, 6 to 74 months). The mean operating time was 430.0 ± 106.7 min, intraoperative blood loss 2018.3 ± 1305.6 ml, transfusion volume 2510.0 ± 1778.1 ml. Complications occurred in 13 patients (21.7%), including poor wound healing (10.0%), deep prosthesis infection (6.7%), hip dislocation (3.3%), screw fracture (1.7%), and interface loosening (1.7%). VAS score improved from 5.5 ± 1.4 to 1.7 ± 1.3, MSTS-93 score from 14.8 ± 2.5 to 23.0 ± 5.6. Implant osseointegration success rate was 98.5% (128/130), with one Type Ba patient experiencing distal prosthesis loosening.
CONCLUSION
The West China classification may supplement the Enneking and Dunham classification, enhancing interdisciplinary communication and surgical outcomes. However, further validation and wider adoption are required to confirm clinical effectiveness.
Topics: Humans; Female; Printing, Three-Dimensional; Male; Retrospective Studies; Adult; Middle Aged; Acetabulum; Bone Neoplasms; Prosthesis Design; Young Adult; Osteotomy; Plastic Surgery Procedures; Adolescent; Aged; Treatment Outcome; Postoperative Complications; Follow-Up Studies; Pelvic Bones
PubMed: 38755628
DOI: 10.1186/s12891-024-07509-8 -
American Society of Clinical Oncology... Jun 2024Although allogeneic hematopoietic cell transplantation (HCT) offers a potential for cure for many patients with advanced hematologic malignancies and bone marrow failure... (Review)
Review
Hematopoietic Stem-Cell Transplantation: Exploring the Latest Advances and Gaps in Disparities, Psychosocial and Symptom Management Interventions, and Chronic Graft-Versus-Host Disease Care.
Although allogeneic hematopoietic cell transplantation (HCT) offers a potential for cure for many patients with advanced hematologic malignancies and bone marrow failure or immunodeficiency syndromes, it is an intensive treatment and accompanied by short- and long-term physical and psychological symptoms requiring specialized care. With substantial advances in therapeutic approaches for HCT and supportive care, HCT survivors experience less morbidity and mortality. However, disparities in both HCT access and outcomes persist, and HCT survivors and their caregivers often lack access to much-needed psychosocial care. Additionally, more medical and psychosocial resources are needed to holistically care for HCT survivors with chronic graft-versus-host disease (GVHD). Hence, this chapter focuses on three areas pertaining to advances and gaps in HCT care: disparities in access to and outcomes of HCT, psychosocial and physical symptom management with supportive care interventions, and GVHD prevention and management.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Hematologic Neoplasms; Chronic Disease; Healthcare Disparities; Disease Management; Bronchiolitis Obliterans Syndrome
PubMed: 38754066
DOI: 10.1200/EDBK_432186 -
ELife May 2024A causal relationship exists among the aging process, organ decay and disfunction, and the occurrence of various diseases including cancer. A genetically engineered...
Long-term hematopoietic transfer of the anti-cancer and lifespan-extending capabilities of a genetically engineered blood system by transplantation of bone marrow mononuclear cells.
A causal relationship exists among the aging process, organ decay and disfunction, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed or (K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/EKLF has been generated that possesses extended lifespan and healthy characteristics, including cancer resistance. We show that the healthy longevity characteristics of the (K74R) mice, as exemplified by their higher anti-cancer capability, are likely gender-, age-, and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of (K74R) mice, could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at a young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild-type NK cells. Targeted/global gene expression profiling analysis has identified changes in the expression of specific proteins, including the immune checkpoint factors PDCD and CD274, and cellular pathways in the leukocytes of the (K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/blood system for long-term anti-cancer and, potentially, for anti-aging.
Topics: Animals; Kruppel-Like Transcription Factors; Mice; Longevity; Killer Cells, Natural; Neoplasms; Genetic Engineering; Bone Marrow Transplantation; Female; Gene Expression Profiling; Male; Mice, Transgenic
PubMed: 38752723
DOI: 10.7554/eLife.88275 -
Technology in Cancer Research &... 2024The objective of this investigation is to evaluate the superiority of dose-volume parameters relying on magnetic resonance imaging (MRI)-defined active bone marrow...
Dose-Volume Parameters of Spared Magnetic Resonance Imaging-Defined Active Bone Marrow Predict Hematologic Toxicity in Pelvic Malignancies Patients Undergoing Radiotherapy: A Cohort Study.
The objective of this investigation is to evaluate the superiority of dose-volume parameters relying on magnetic resonance imaging (MRI)-defined active bone marrow (ABM) over those based on total bone marrow (TBM) contoured via CT in the prediction of hematologic toxicity (HT) occurrence among patients with pelvic malignancies undergoing radiotherapy. The clinical data of 116 patients with pelvic malignancies treated with pelvic radiotherapy were analyzed retrospectively. The ABM areas on T1-weighted MRI were contoured. The statistical significance between TBM and ABM dose-volume measures was assessed through the utilization of either Student's t-test or Wilcoxon signed rank test. Logistic and linear regression models were employed to analyze the correlation between dose-volume parameters (V5-V50) and HT occurrence in pelvic ABM and TBM. Receiver operating characteristic (ROC) curves were used to compare predictors of HT2+. There were significant differences in dosimetric parameters between ABM and TBM. Logistic regression analysis showed that ABM V5, ABM V10, ABM V15, ABM V20, and TBM V5 were significantly associated with the occurrence of HT2+ in pelvic malignancies. Linear regression analysis showed that ABM V5, ABM V10, and ABM V15 were significantly associated with white blood cell (WBC), absolute neutrophil count (ANC), hemoglobin (Hb), and lymphocyte (Lym) nadir. ABM V5, ABM V10, ABM V15, and ABM V30 were predictive of HT2+. More accurate prediction of HT in patients receiving pelvic radiotherapy may be achieved by relying on dose-volume parameters of MRI-based ABM. Further prospective studies are needed to confirm this.
Topics: Humans; Female; Bone Marrow; Magnetic Resonance Imaging; Male; Middle Aged; Radiotherapy Dosage; Pelvic Neoplasms; Aged; Adult; Retrospective Studies; Radiotherapy Planning, Computer-Assisted; Radiation Injuries; ROC Curve; Aged, 80 and over; Hematologic Diseases
PubMed: 38752234
DOI: 10.1177/15330338241255283 -
JPMA. the Journal of the Pakistan... Apr 2024Enbloc Sacrectomy is the procedure of choice for aggressive sacral lesions but not widely practiced in Pakistan, both by Neurosurgeons and Orthopaedic surgeons. Only one...
Enbloc Sacrectomy is the procedure of choice for aggressive sacral lesions but not widely practiced in Pakistan, both by Neurosurgeons and Orthopaedic surgeons. Only one case has been mentioned in indexed local literature so far and that too not operated in Pakistan. The case of a 27 year old neurologically intact male is presented. He had a huge residual mass and midline non-healing wound after two attempts at intralesional debulking and one full course of local irradiation. He presented to the Mayo Hospital, Lahore on 29th December 2021 for a redo surgery of sacral chordoma. A marginal excision was achieved utilizing posterior only approach. This case will help to understand the key steps in enbloc mid-Sacrectomy and importance of involving multidisciplinary team for ensuring adequate wound closure.
Topics: Humans; Chordoma; Male; Sacrum; Adult; Spinal Neoplasms; Reoperation
PubMed: 38751282
DOI: 10.47391/JPMA.9145 -
Journal of Nanobiotechnology May 2024The complexity of repairing large segment defects and eradicating residual tumor cell puts the osteosarcoma clinical management challenging. Current biomaterial design...
The complexity of repairing large segment defects and eradicating residual tumor cell puts the osteosarcoma clinical management challenging. Current biomaterial design often overlooks the crucial role of precisely regulating innervation in bone regeneration. Here, we develop a Germanium Selenium (GeSe) co-doped polylactic acid (PLA) nanofiber membrane-coated tricalcium phosphate bioceramic scaffold (TCP-PLA/GeSe) that mimics the bone-periosteum structure. This biomimetic scaffold offers a dual functionality, combining piezoelectric and photothermal conversion capabilities while remaining biodegradable. When subjected to ultrasound irradiation, the US-electric stimulation of TCP-PLA/GeSe enables spatiotemporal control of neurogenic differentiation. This feature supports early innervation during bone formation, promoting early neurogenic differentiation of Schwann cells (SCs) by increasing intracellular Ca and subsequently activating the PI3K-Akt and Ras signaling pathways. The biomimetic scaffold also demonstrates exceptional osteogenic differentiation potential under ultrasound irradiation. In rabbit model of large segment bone defects, the TCP-PLA/GeSe demonstrates promoted osteogenesis and nerve fibre ingrowth. The combined attributes of high photothermal conversion capacity and the sustained release of anti-tumor selenium from the TCP-PLA/GeSe enable the synergistic eradication of osteosarcoma both in vitro and in vivo. This strategy provides new insights on designing advanced biomaterials of repairing large segment bone defect and osteosarcoma.
Topics: Osteosarcoma; Animals; Bone Regeneration; Tissue Scaffolds; Rabbits; Calcium Phosphates; Osteogenesis; Polyesters; Humans; Cell Differentiation; Bone Neoplasms; Cell Line, Tumor; Biomimetic Materials; Schwann Cells; Nanofibers; Biocompatible Materials; Selenium
PubMed: 38750519
DOI: 10.1186/s12951-024-02430-7