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Journal of Extracellular Vesicles Jul 2024Extracellular vesicles have gained wide momentum as potential therapeutics for osteoarthritis, a highly prevalent chronic disease that still lacks an approved treatment.... (Review)
Review
Extracellular vesicles have gained wide momentum as potential therapeutics for osteoarthritis, a highly prevalent chronic disease that still lacks an approved treatment. The membrane-bound vesicles are secreted by all cells carrying different cargos that can serve as both disease biomarkers and disease modifiers. Nonetheless, despite a significant peak in research regarding EVs as OA therapeutics, clinical implementation seems distant. In addition to scalability and standardization challenges, researchers often omit to focus on and consider the proper tropism of the vesicles, the practicality and relevance of their source, their low native therapeutic efficacy, and whether they address the disease as a whole. These considerations are necessary to better understand EVs in a clinical light and have been comprehensively discussed and ultimately summarized in this review into a conceptualized framework termed the nanodiamond concept. Future perspectives are also discussed, and alternatives are presented to address some of the challenges and concerns.
Topics: Humans; Extracellular Vesicles; Osteoarthritis; Biomarkers; Animals
PubMed: 38943211
DOI: 10.1002/jev2.12435 -
Cellular & Molecular Biology Letters Jun 2024Nasopharyngeal carcinoma (NPC), primarily found in the southern region of China, is a malignant tumor known for its highly metastatic characteristics. The high mortality...
Nasopharyngeal carcinoma (NPC), primarily found in the southern region of China, is a malignant tumor known for its highly metastatic characteristics. The high mortality rates caused by the distant metastasis and disease recurrence remain unsolved clinical problems. In clinic, the berberine (BBR) compound has widely been in NPC therapy to decrease metastasis and disease recurrence, and BBR was documented as a main component with multiple anti-NPC effects. However, the mechanism by which BBR inhibits the growth and metastasis of nasopharyngeal carcinoma remains elusive. Herein, we show that BBR effectively inhibits the growth, metastasis, and invasion of NPC via inducing a specific super enhancer (SE). From a mechanistic perspective, the RNA sequencing (RNA-seq) results suggest that the RAS-RAF1-MEK1/2-ERK1/2 signaling pathway, activated by the epidermal growth factor receptor (EGFR), plays a significant role in BBR-induced autophagy in NPC. Blockading of autophagy markedly attenuated the effect of BBR-mediated NPC cell growth and metastasis inhibition. Notably, BBR increased the expression of EGFR by transcription, and knockout of EGFR significantly inhibited BBR-induced microtubule associated protein 1 light chain 3 (LC3)-II increase and p62 inhibition, proposing that EGFR plays a pivotal role in BBR-induced autophagy in NPC. Chromatin immunoprecipitation sequencing (ChIP-seq) results found that a specific SE existed only in NPC cells treated with BBR. This SE knockdown markedly repressed the expression of EGFR and phosphorylated EGFR (EGFR-p) and reversed the inhibition of BBR on NPC proliferation, metastasis, and invasion. Furthermore, BBR-specific SE may trigger autophagy by enhancing EGFR gene transcription, thereby upregulating the RAS-RAF1-MEK1/2-ERK1/2 signaling pathway. In addition, in vivo BBR effectively inhibited NPC cells growth and metastasis, following an increase LC3 and EGFR and a decrease p62. Collectively, this study identifies a novel BBR-special SE and established a new epigenetic paradigm, by which BBR regulates autophagy, inhibits proliferation, metastasis, and invasion. It provides a rationale for BBR application as the treatment regime in NPC therapy in future.
Topics: Berberine; Nasopharyngeal Carcinoma; Autophagy; Humans; ErbB Receptors; Cell Line, Tumor; Nasopharyngeal Neoplasms; MAP Kinase Signaling System; Animals; Proto-Oncogene Proteins c-raf; Cell Proliferation; ras Proteins; Mice; Gene Expression Regulation, Neoplastic; Enhancer Elements, Genetic; Mice, Nude
PubMed: 38943090
DOI: 10.1186/s11658-024-00607-4 -
Communications Biology Jun 2024The Mycoplasma Immunoglobulin Binding/Protease (MIB-MIP) system is a candidate 'virulence factor present in multiple pathogenic species of the Mollicutes, including the...
The Mycoplasma Immunoglobulin Binding/Protease (MIB-MIP) system is a candidate 'virulence factor present in multiple pathogenic species of the Mollicutes, including the fast-growing species Mycoplasma feriruminatoris. The MIB-MIP system cleaves the heavy chain of host immunoglobulins, hence affecting antigen-antibody interactions and potentially facilitating immune evasion. In this work, using -omics technologies and 5'RACE, we show that the four copies of the M. feriruminatoris MIB-MIP system have different expression levels and are transcribed as operons controlled by four different promoters. Individual MIB-MIP gene pairs of M. feriruminatoris and other Mollicutes were introduced in an engineered M. feriruminatoris strain devoid of MIB-MIP genes and were tested for their functionality using newly developed oriC-based plasmids. The two proteins are functionally expressed at the surface of M. feriruminatoris, which confirms the possibility to display large membrane-associated proteins in this bacterium. However, functional expression of heterologous MIB-MIP systems introduced in this engineered strain from phylogenetically distant porcine Mollicutes like Mesomycoplasma hyorhinis or Mesomycoplasma hyopneumoniae could not be achieved. Finally, since M. feriruminatoris is a candidate for biomedical applications such as drug delivery, we confirmed its safety in vivo in domestic goats, which are the closest livestock relatives to its native host the Alpine ibex.
Topics: Bacterial Vaccines; Mycoplasma; Animals; Bacterial Proteins; Immunoglobulins; Gene Expression Regulation, Bacterial; Mycoplasma Infections; Goats
PubMed: 38942984
DOI: 10.1038/s42003-024-06497-8 -
Korean Journal of Radiology Jul 2024To develop and validate a preoperative risk score incorporating carbohydrate antigen (CA) 19-9, CT, and fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT variables to...
Predicting Recurrence-Free Survival After Upfront Surgery in Resectable Pancreatic Ductal Adenocarcinoma: A Preoperative Risk Score Based on CA 19-9, CT, and F-FDG PET/CT.
OBJECTIVE
To develop and validate a preoperative risk score incorporating carbohydrate antigen (CA) 19-9, CT, and fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT variables to predict recurrence-free survival (RFS) after upfront surgery in patients with resectable pancreatic ductal adenocarcinoma (PDAC).
MATERIALS AND METHODS
Patients with resectable PDAC who underwent upfront surgery between 2014 and 2017 (development set) or between 2018 and 2019 (test set) were retrospectively evaluated. In the development set, a risk-scoring system was developed using the multivariable Cox proportional hazards model, including variables associated with RFS. In the test set, the performance of the risk score was evaluated using the Harrell C-index and compared with that of the postoperative pathological tumor stage.
RESULTS
A total of 529 patients, including 335 (198 male; mean age ± standard deviation, 64 ± 9 years) and 194 (103 male; mean age, 66 ± 9 years) patients in the development and test sets, respectively, were evaluated. The risk score included five variables predicting RFS: tumor size (hazard ratio [HR], 1.29 per 1 cm increment; < 0.001), maximal standardized uptake values of tumor ≥ 5.2 (HR, 1.29; = 0.06), suspicious regional lymph nodes (HR, 1.43; = 0.02), possible distant metastasis on F-FDG PET/CT (HR, 2.32; = 0.03), and CA 19-9 (HR, 1.02 per 100 U/mL increment; = 0.002). In the test set, the risk score showed good performance in predicting RFS (C-index, 0.61), similar to that of the pathologic tumor stage (C-index, 0.64; = 0.17).
CONCLUSION
The proposed risk score based on preoperative CA 19-9, CT, and F-FDG PET/CT variables may have clinical utility in selecting high-risk patients with resectable PDAC.
Topics: Humans; Male; Fluorodeoxyglucose F18; Female; Positron Emission Tomography Computed Tomography; Middle Aged; Carcinoma, Pancreatic Ductal; Aged; Pancreatic Neoplasms; Retrospective Studies; Radiopharmaceuticals; CA-19-9 Antigen; Tomography, X-Ray Computed; Neoplasm Recurrence, Local; Risk Assessment; Disease-Free Survival; Predictive Value of Tests
PubMed: 38942458
DOI: 10.3348/kjr.2023.1235 -
Science Advances Jun 2024Seismic observations of impacts on Mars indicate a higher impact flux than previously measured. Using six confirmed seismic impact detections near the NASA InSight...
Seismic observations of impacts on Mars indicate a higher impact flux than previously measured. Using six confirmed seismic impact detections near the NASA InSight lander and two distant large impacts, we calculate appropriate scalings to compare these rates with lunar-based chronology models. We also update the impact rate from orbital observations using the most recent catalog of new craters on Mars. The snapshot of the current impact rate at Mars recorded seismically is higher than that found using orbital detections alone. The measured rates differ between a factor of 2 and 10, depending on the diameter, although the sample size of seismically detected impacts is small. The close timing of the two largest new impacts found on Mars in the past few decades indicates either a heightened impact rate or a low-probability temporal coincidence, perhaps representing recent fragmentation of a parent body. We conclude that seismic methods of detecting current impacts offer a more complete dataset than orbital imaging.
PubMed: 38941463
DOI: 10.1126/sciadv.adk7615 -
ELife Jun 2024Genetic diversity is a hallmark of RNA viruses and the basis for their evolutionary success. Taking advantage of the uniquely large genomic database of SARS-CoV-2, we...
Genetic diversity is a hallmark of RNA viruses and the basis for their evolutionary success. Taking advantage of the uniquely large genomic database of SARS-CoV-2, we examine the impact of mutations across the spectrum of viable amino acid sequences on the biophysical phenotypes of the highly expressed and multifunctional nucleocapsid protein. We find variation in the physicochemical parameters of its extended intrinsically disordered regions (IDRs) sufficient to allow local plasticity, but also observe functional constraints that similarly occur in related coronaviruses. In biophysical experiments with several N-protein species carrying mutations associated with major variants, we find that point mutations in the IDRs can have nonlocal impact and modulate thermodynamic stability, secondary structure, protein oligomeric state, particle formation, and liquid-liquid phase separation. In the Omicron variant, distant mutations in different IDRs have compensatory effects in shifting a delicate balance of interactions controlling protein assembly properties, and include the creation of a new protein-protein interaction interface in the N-terminal IDR through the defining P13L mutation. A picture emerges where genetic diversity is accompanied by significant variation in biophysical characteristics of functional N-protein species, in particular in the IDRs.
Topics: SARS-CoV-2; Coronavirus Nucleocapsid Proteins; Mutation; COVID-19; Humans; Intrinsically Disordered Proteins; Phosphoproteins; Nucleocapsid Proteins; Thermodynamics; Protein Stability
PubMed: 38941236
DOI: 10.7554/eLife.94836 -
Alternative Therapies in Health and... Jun 2024Colorectal cancer is a malignant tumor with high mortality, but is hard to detect at its early stage. Recent studies highlighted the crucial roles of Ezrin protein and...
OBJECTIVE
Colorectal cancer is a malignant tumor with high mortality, but is hard to detect at its early stage. Recent studies highlighted the crucial roles of Ezrin protein and MMP-9 in the development and malignancy of colorectal cancer, but Ezrin protein and MMP-9 in early diagnosis of colorectal cancer require further investigation. Therefore, we aimed to investigate their roles in the occurrence and metastasis of colorectal cancer, and to analyze their clinical significance in diagnosing and treating colorectal cancer.
METHOD
The diagnosis of collected colorectal cancer tissue and adjacent tissue samples from colorectal cancer patients confirmed by clinical symptoms was performed using Hematoxylin Eosin staining. The expression levels of Ezrin and MMP-9 in 50 colorectal cancer tissue and 50 cases adjacent colorectal cancer tissue were detected by the immuno-histochemical MaxVision method. The relationship between the positive expression rate of Ezrin and MMP-9 in colorectal cancer tissue and clinical pathological factors was analyzed, and the correlation between Ezrin and MMP-9 was examined.
RESULTS
The positive expression rate of Ezrin in colorectal cancer tissue (78%) was significantly higher compared to adjacent non-cancerous tissues (6.0%) (P < .05). There was no significant correlation of gender/age and Ezrin/MMP-9 expressions (P > .05). The expression level of Ezrin exhibited statistically significant differences in the pathological factors including tumor diameter, depth of invasion, degree of differentiation, presence or absence of lymph node metastasis, and distant metastasis (P < .05). Additionally, the positive expression rate of MMP-9 in colorectal cancer tissue (76%) was markedly elevated compared to adjacent tissues (8.0%) (P < .05). The expression level of MMP-9 showed statistically significant differences in the pathological factors including tumor diameter, depth of invasion, degree of differentiation, presence or absence of lymph node metastasis, and distant metastasis (P < .05). In addition, the expression of Ezrin and MMP-9 in colorectal cancer tissue showed a significant positive correlation (r=0.637, P < .01).
CONCLUSION
Ezrin and MMP-9 may synergistically participate in the occurrence, invasion, and metastasis of colorectal cancer. The combined assessment of Ezrin and MMP-9 expression levels in colorectal cancer patients holds significant potential for clinical diagnosis and personalized therapeutic applications.
PubMed: 38940787
DOI: No ID Found -
Oncology Letters Aug 2024Thymic epithelial tumors (TETs) are rare and the major symptoms are not obvious until the tumor progresses to a relatively large size and compresses the surrounding...
Thymic epithelial tumors (TETs) are rare and the major symptoms are not obvious until the tumor progresses to a relatively large size and compresses the surrounding organs. As its growth is aggressive and it metastasizes to distant organs, it is important to find novel effective therapies. Lenvatinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, is approved as a drug therapy for thymic carcinoma (TC); however, although it is a molecular targeted therapy, there are no obvious predictors of therapeutic efficacy. The present study aimed to assess the association between clinicopathological factors and the protein expression of VEGFR, which is associated with tumor aggressiveness and the efficacy of VEGFR inhibitors. The VEGFR-2 protein expression was evaluated in 144 patients with TETs who underwent surgical resection. The present study assessed whether the expression of VEGFR-2 protein was associated with TET classification and pathological stage, progression-free survival and overall survival (OS). A total of 94 cases (65.2%) were positive for VEGFR-2 protein. The expression of VEGFR-2 was higher in the more aggressive type B3 thymoma and TC (88.5%) than in types A, AB, B1 and B2 thymoma (60.2%). The 5-year OS rate for the overall population was 53.1%. The 5-year OS rates of patients with negative VEGFR-2 staining score values (66.5%) were significantly longer than in patients with positive VEGFR-2 staining score values (42.5%; P=0.000078). Furthermore, the pathological stage was the only factor significantly associated with OS in multivariate analysis. The results of the present study suggest the possibility that the indications for VEGF inhibitor therapy could be extended to type B3 thymoma.
PubMed: 38939624
DOI: 10.3892/ol.2024.14516 -
Gynecologic Oncology Reports Aug 2024Endometrial large cell neuroendocrine carcinoma (LCNEC) is a highly malignant tumor that presents with neuroendocrine function. It is difficult to diagnose at an early...
Endometrial large cell neuroendocrine carcinoma (LCNEC) is a highly malignant tumor that presents with neuroendocrine function. It is difficult to diagnose at an early stage. Moreover, the diagnosis depends on the pathological and immunohistochemical findings. It is also prone to distant metastasis, but is difficult to treat and shows poor prognosis. Presently, there exists no unified treatment plan, and the prognosis of this disease is also poor. We reported here an analysis and literature review of a case of endometrial LCNEC to facilitate the comprehension of this disease and provide help toward clinical diagnosis and treatment.
PubMed: 38939507
DOI: 10.1016/j.gore.2024.101429 -
BioMedicine 2024Metastasis of breast cancer cells to distant sites including lungs, liver, lymph node, brain and many more have substantially affected the overall survival outcome and...
BACKGROUND
Metastasis of breast cancer cells to distant sites including lungs, liver, lymph node, brain and many more have substantially affected the overall survival outcome and distant metastasis free survival rate amongst the diseased individuals. Several pre-clinical and clinical studies were carried out to determine the potency of vigorous inhibitors but they extensively deteriorated the patient's quality of life. Hence, there exists an urgent need to explore potent natural remedy to fight against metastatic breast cancer.
METHODS
Ayurvedic medicinal plants documented in literature for their ability to fight against breast cancer was screened and their respective active moieties were evaluated to exert inhibitory effect against MMP9. Drug like efficacy of phytochemicals were determined using Molecular docking, MD Simulation, ADMET and MM-PBSA and were further compared with synthetic analogs i.e. Doxycycline.
RESULTS
Out of 1000 phytochemicals, 12 exerted highest binding affinity (BA) even more than -9.0 kcal/mol that was significantly higher in comparison to Doxycycline which exhibited BA of -7.3 kcal/mol. In comparison to 37 × 30 × 37 Å, 53 × 45 × 66 Å offered best binding site and the highest BA was exhibited by Viscosalactone at LYS104, ASP185, MET338, LEU39, ASN38. During MD Simulation, Viscosalactone-MMP9 complex remained stable for 20 ns and the kinetic, electrostatic and potential energies were observed to be better than Doxycycline. Furthermore, Viscosalactone obtained from justified the Lipinski's Rule of 5.
CONCLUSION
Viscosalactone obtained from may act as promising drug candidate to fight against metastatic breast cancer.
PubMed: 38939099
DOI: 10.37796/2211-8039.1448