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Polymethyl methacrylate (PMMA) based biomaterials have been widely utilized in clinics. However, currently, PMMA catalyzed by benzoyl peroxide (BPO) exhibits disquieting disadvantages including an exothermic polymerization reaction and a lack of bioactivity. Here, we first designed three industrial-scale synthesis methods for high-purity butoxydibutylborane (BODBB), achieving purity levels greater than 95% (maximum: 97.6%) and ensuring excellent fire safety. By utilizing BODBB as a catalyst, the highest polymerization temperature of PMMA bone cement (PMMA-BODBB) reached only 36.05 °C, ensuring that no thermal damage occurred after implantation. Compared to PMMA catalyzed by BPO and partially oxidized tributylborane (TBBO, catalyst of Super Bond C&B), PMMA-BODBB exhibited superior cell adhesion, proliferation, and osteogenesis, attributed to the reduced release of free radicals and toxic monomer, and moderate bioactive boron release. After injection into a 5 mm defect in the rat cranial bone, PMMA-BODBB demonstrated the highest level of osteointegration. This work not only presents an industrial-scale synthesis of high-purity BODBB, but also offers an innovative PMMA biomaterial system with intrinsic biocompatibility and osseointegration, paving the way for the next generation of PMMA-based biomaterials with broader applications.
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Background: This retrospective cohort study explores a practical approach to acquiring pathogenic microorganisms in patients with bone and joint infections. Methods: From Aug 2018 to Mar 2022, 68 consecutive patients (87 cultures) with bone and joint infection were recruited in this study. All cultures followed the Peking University First Hospital Procedure of Culturing Pathogenic microorganisms for bone and joint infection. Tissue samples were obtained through fluoroscopy-guided biopsy or open debridement. Tissue samples were divided into manual homogenization (MH), manual mixture (MM), and pathological examination. The baseline, antibiotic exposure, laboratory, surgical, and microbial data were reviewed. Independent sample T-test, Mann-Whitney U-test, and Chi-square test were used to detect the difference between patients who received different processing measures. Results: The average age was 55.8±2.4 years old. Thirty-nine patients were male. The total positive culture rate of the manual homogenization group was 80.5% (70/87). Thirty-five patients had mixed infections with more than one microorganism cultured. Staphylococci accounted for 60.23% of all microorganisms. Staphylococcus aureus (18.2%) and Staphylococcus epidermidis (15.9%) were the two most common bacteria cultured in this study. Patients with positive culture in the manual mixture group had significantly higher WBC (p = 0.006), NE% (p = 0.024), ESR (p = 0.003), CRP (p = 0.020) and IL6 (0.050) compared to patients with negative culture. After tissue homogenization, only ESR is still statistically different. Patients without SIRS had a low positive culture rate (59.4%). Tissue homogenization could significantly increase the positive culture rate of patients without SIRS. Pre-culture antibiotic exposure was not an independent risk factor for culture results. Conclusion: Peking University First Hospital Procedure for Culturing Pathogenic microorganisms for Bone and Joint Infections was a practical approach for obtaining pathogenic microorganisms.
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The purpose of this study was to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of frunexian (formerly known as EP-7041 and HSK36273) injection, a small molecule inhibitor of activated coagulation factor XI (FXIa), in healthy Chinese adult volunteers. This study was a randomized, placebo- and positive-controlled, sequential, ascending-dose (0.3/0.6/1.0/1.5/2.25 mg/kg/h) study of 5-day continuous intravenous infusions of frunexian. Frunexian administration exhibited an acceptable safety profile with no bleeding events. Steady state was rapidly reached with a median time ranging from 1.02 to 1.50 h. The mean half-life ranged from 1.15 to 1.43 h. Frunexian plasma concentration at a steady state and area under the concentration-time curve exhibited dose-proportional increases. The dose-escalation study of frunexian demonstrated its progressively enhanced capacities to prolong activated partial thromboplastin time (aPTT) and inhibit FXIa activity. The correlations between PK and PD biomarkers (aPTT/baseline and FXI clotting activity/baseline) were described by the two Emax models, with the EC50 values of 8940 and 1300 ng/mL, respectively. Frunexian exhibits good safety and PK/PD properties, suggesting it is a promising candidate for anticoagulant drug.
Subject(s)
Anticoagulants , Blood Coagulation , Adult , Humans , Partial Thromboplastin Time , Healthy Volunteers , China , Double-Blind Method , Dose-Response Relationship, DrugABSTRACT
BACKGROUND: This study aimed to evaluate the perioperative safety and efficacy of the Mini-open and trans-tubular approach in patients with spinal metastases who underwent decompression surgery. METHODS: 37 consecutive patients with spinal metastases who underwent decompression surgery through a Mini-open or trans-tubular approach were retrospectively reviewed between June 2017 and June 2022. Thirty-four patients were included in this study. 19 underwent decompression surgery through the Mini-open approach, and 15 underwent the Trans-tubular approach. T-test and chi-square test were used to evaluate the difference between baseline data and primary and secondary outcomes. RESULTS: Baseline characteristics did not differ significantly between Trans-tubular and Mini-open groups except for the Ambulatory status (P < 0.001). There was no significant difference in blood loss between the two groups (P = 0.061). Operative time, intraoperative blood transfusion, intraoperative complication (dural tear), and postoperative hospitalization were comparable in the two groups (P > 0.05). The trans-tubular group had significantly less amount of postoperative drainage (133.5 ± 30.9 ml vs. 364.5 ± 64.2 ml, p = 0.003), and the time of drainage (3.1 ± 0.2 days vs. 4.6 ± 0.5 days, p = 0.019) compared with Mini-open group (P < 0.05). Sub-group analysis showed that for patients with hypo-vascular tumors, the Trans-tubular group had significantly less blood loss than the Mini-open group (951.1 ± 171.7 ml vs. 1599.1 ± 105.7 ml, P = 0.026). CONCLUSIONS: Decompression through Mini-open or Trans-tubular was safe and effective for patients with spinal metastases. The trans-tubular approach might be more suitable for patients with hypo-vascular tumors.
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Spinal Neoplasms , Vascular Neoplasms , Humans , Retrospective Studies , Spinal Neoplasms/surgery , Spinal Neoplasms/secondary , Treatment Outcome , DecompressionABSTRACT
Efficient deep-water offshore wind power installation platforms with a pressurized self-elevating mat are a new type of equipment used for installing offshore wind turbines. However, the unstable internal pressure of the pressurized self-elevating mat can cause serious harm to the platform. This paper studies the pneumatic control system of the self-elevating mat to improve the precision of its pressure control. According to the pneumatic control system structure of the self-elevating mat, the pneumatic model of the self-elevating mat is established, and a conventional PID controller and fuzzy PID controller are designed and established. It can be seen via Simulink simulation that the fuzzy PID controller has a smaller adjustment time and overshoot, but its anti-interference ability is relatively weak. The membership degree and fuzzy rules of the fuzzy PID controller are optimized using a neural network algorithm, and a fuzzy neural network PID controller based on BP neural network optimization is proposed. The simulation results show that the overshoot of the optimized controller is reduced by 9.71% and the stability time is reduced by 68.9% compared with the fuzzy PID. Finally, the experiment verifies that the fuzzy neural network PID controller has a faster response speed and smaller overshoot, which improves the pressure control accuracy and robustness of the self-elevating mat and provides a scientific basis for the engineering applications of the self-elevating mat.
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2D materials that can provide long-range ordered channels in thin-film form are highly desirable for proton exchange membranes (PEMs). Covalent organic framework nanosheets (CONs) are promising 2D materials possessing intrinsic porosity and high processability. However, the potential of CONs in PEMs is limited by loose sheet stacking and interfacial grain boundary, which lead to unsatisfied mechanical property and discontinuous conduction pathway. Herein, chitosan (CS), a natural polymer with rich NH2 groups, is designed as the linker of dual-sulfonate CONs (CON-2(SO3 H)) to obtain CON-2(SO3 H)-based membrane. Ultrathin CON-2(SO3 H) with high crystallinity and large lateral size is synthesized at water-octanoic acid interface. The high flexibility of CS chains and their electrostatic interactions with SO3 H groups of CON-2(SO3 H) enable effective connection of CON-2(SO3 H), thus endowing membrane dense structure and exceptional stability. The stacked CON-2(SO3 H) constructs regular hydrophilic nanochannels containing high-density SO3 H groups, and the electrostatic interactions between CON-2(SO3 H) and CS form interfacial acid-base pairs transfer channels. Consequently, CON-2(SO3 H)@CS membrane simultaneously achieves superior proton conductivity of 353 mS cm-1 (under 80 °C hydrated condition) and tensile strength of 95 MPa. This work highlights the advantages of proton-conducting porous CON-2(SO3 H) in advanced PEMs and paves a way in fabricating robust CON-based membranes for various applications.
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Objective: This study aimed to investigate the effects of manual homogenization on the sensitivity of microbiological culture for patients with pyogenic spondylitis. Methods: From October 2018 to March 2021, patients undergoing fluoroscopy-guided biopsy or open debridement due to pyogenic spondylitis were recruited. Their demographic data and baseline characteristics were recorded. Tissue samples were obtained through fluoroscopy-guided biopsy or open debridement. Tissue samples were divided into three parts: manual homogenization (MH), manual mixture (MM), and pathological examination. Sterile normal saline was set as the negative control to exclude false-positive culture results. The Chi-square test was used to detect the difference of microbiological culture results. Results: Twenty-four consecutive patients (33 tissue cultures) with pyogenic spondylitis treated in our department between October 2018 and March 2021 were recruited in this study. The average age was 61.7±3.2 years old and 10 patients were female. The MH group had a significantly higher positive rate compared with the MM group in aerobic conditions: 78.8% (26 isolates) vs 54.5% (18 isolates), P=0.037 and anaerobic condition: 63.6% (21 isolates) vs 39.4% (13 isolates), P=0.049. The results of subgroup analyses showed that MH could improve the culture sensitivity for patients with previous antibiotics use and without paravertebral abscesses but not reach a significant level on statistics. Conclusion: Based on the present study, manual homogenization could improve the sensitivity of microbiological cultures for patients with pyogenic spondylitis.
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BACKGROUND: Although, micropeptides encoded by non-coding RNA have been shown to have an important role in a variety of tumors processes, there have been no reports on micropeptide in renal cell carcinoma (RCC). Based on the micropeptide MIAC (micropeptide inhibiting actin cytoskeleton) discovered and named in the previous work, this study screened its tumor spectrum, and explored its mechanism of action and potential diagnosis and treatment value in the occurrence and development of renal carcinoma. METHODS: The clinical significance of MIAC in RCC was explored by bioinformatics analysis through high-throughput RNA-seq data from 530 patients with kidney renal clear cell carcinoma (KIRC) in the TCGA database, and the detection of clinical samples of 70 cases of kidney cancer. In vitro and in vivo experiments to determine the role of MIAC in renal carcinoma cell growth and metastasis; High-throughput transcriptomics, western blotting, immunoprecipitation, molecular docking, affinity experiments, and Streptavidin pulldown experiments identify MIAC direct binding protein and key regulatory pathways. RESULTS: The analysis of 600 renal carcinoma samples from different sources revealed that the expression level of MIAC is significantly decreased, and corelated with the prognosis and clinical stage of tumors in patients with renal carcinoma. Overexpression of MIAC in renal carcinoma cells can significantly inhibit the proliferation and migration ability, promote apoptosis of renal carcinoma cells, and affect the distribution of cells at various stages. After knocking down MIAC, the trend is reversed. In vivo experiments have found that MIAC overexpression inhibit the growth and metastasis of RCC, while the synthetized MIAC peptides can significantly inhibit the occurrence and development of RCC in vitro and in vivo. Further mechanistic studies have demonstrated that MIAC directly bind to AQP2 protein, inhibit EREG/EGFR expression and activate downstream pathways PI3K/AKT and MAPK to achieve anti-tumor effects. CONCLUSIONS: This study revealed for the first time the tumor suppressor potential of the lncRNA-encoded micropeptide MIAC in RCC, which inhibits the activation of the EREG/EGFR signaling pathway by direct binding to AQP2 protein, thereby inhibiting renal carcinoma progression and metastasis. This result emphasizes that the micropeptide MIAC can provide a new strategy for the diagnosis and treatment of RCC.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , RNA, Long Noncoding , Aquaporin 2/genetics , Aquaporin 2/metabolism , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Epiregulin , ErbB Receptors/genetics , ErbB Receptors/metabolism , Gene Expression Regulation, Neoplastic , Humans , Kidney Neoplasms/pathology , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Long Noncoding/genetics , Signal Transduction , Streptavidin/genetics , Streptavidin/metabolism , Streptavidin/therapeutic useABSTRACT
Introduction: Flat dosing regimen has recently been approved for programmed death receptor-1 (PD-1) inhibitors including toripalimab, nivolumab and pembrolizumab. The objective of this study is to provide pharmacological evidence for a flat dosing regimen of toripalimab by assessing the efficacy and safety profile of a 240 mg Q3W flat dose relative to the currently approved 3 mg/kg Q2W. Methods: A population pharmacokinetic (PopPK) model was established based on 1,014 evaluable patients in 13 clinical studies. The exposure-objective response rate (ORR, n = 234) and exposure-safety (n = 152) analyses were performed by logistic regression. Three safety endpoints including grade ≥ 3 adverse events (AEs), treatment-related grade ≥ 3 AEs, and AEs leading to study drug discontinuation were evaluated. Progression-free survival (PFS, n = 234) was evaluated using a Cox proportional hazard model with the Kaplan-Meier survival curve. Results: The PK profiles of toripalimab are best described by a two-compartment model with time-varying clearance characterized by a sigmoidal maximum effect (Emax) function. Simulations for the first dose and steady-state exposures for the 240 mg Q3W dosing regimen were comparable to those for the 3 mg/kg Q2W dosing regimen with 95% exposure coverage ranging from 88% to 96%. The exposure-safety analysis showed that the probability of an adverse event occurring did not increase with increases in toripalimab exposure. A flat exposure-response relationship for ORR was identified. The Kaplan-Meier survival curve showed that exposure was a predictor for PFS; however, no difference in treatment benefit was demonstrated across exposure quantiles using a Cox proportional hazard model. Discussion: This study revealed that toripalimab exposure of 240 mg Q3W dosing regimen was comparable to 3 mg/kg Q2W dosing regimen. The safety and efficacy E-R results of 240 mg Q3W is flat. Hence, the 240 mg Q3W dosing regimen is determined to be a preferred therapeutic dosage for toripalimab due to the convenience of flat dose.
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BACKGROUND: The study aimed to identify the risk factors of cement leakage following percutaneous vertebroplasty for spinal metastases. METHODS: 230 consecutive patients with 530 vertebrae were retrospectively reviewed. Characteristics including age, primary cancer, location, pathological fracture, the integrity of the posterior wall, and the volume of bone cement were considered as potential risk factors. Cement leakage was evaluated by postoperative imaging examination and classified into three subtypes with different potential sequelae: spinal canal leakage, intravascular leakage around vertebrae, intradiscal and paravertebral leakage. Univariate and multivariate analyses were used to assess the risk factors. RESULTS: Leakage was detected in 185 vertebrae (34.9%), 18.3% for intradiscal and paravertebral, 13.2% for intravascular around vertebrae, and 7.0% for spinal canal. Multivariate analysis showed that incomplete posterior wall (P = 0.001) and breast cancer (P = 0.015) were strong predictive factors for spinal canal leakage, incomplete posterior wall (P = 0.024) was for intravascular leakage around vertebrae, thoracic (P = 0.010) and pathological fracture (P = 0.000) were for intradiscal and paravertebral leakage. CONCLUSIONS: Our findings suggest that cement leakage is common following percutaneous vertebroplasty for spinal metastases. The incomplete posterior wall is an unfavourable factor for intravascular leakage around vertebrae. Vertebrae with incomplete posterior wall and breast cancer metastases are more likely to develop spinal canal leakage.
Subject(s)
Fractures, Compression , Spinal Fractures , Spinal Neoplasms , Vertebroplasty , Bone Cements , Humans , Retrospective Studies , Risk Factors , Spinal Fractures/diagnostic imaging , Spinal Fractures/etiology , Spinal Fractures/surgery , Spinal Neoplasms/diagnostic imaging , Spinal Neoplasms/surgery , Vertebroplasty/adverse effectsABSTRACT
BACKGROUND: This study aimed to evaluate the perioperative safety and efficacy of minimally invasive tubular surgery for patients with spinal metastasis. METHODS: A total of 161 consecutive patients with spinal metastasis between June 2017 and June 2020 were retrospectively reviewed. A total of 36 patients were included in this study, 14 patients underwent minimally invasive tubular surgery (M), and 22 patients underwent conventional surgery (C). T-test and chi-square tests were used to evaluate demographic and perioperative data differences between the two groups. RESULTS: Baseline characteristics did not differ significantly between M and C groups except for the SINS (p=0.002) and preoperative Alb (p=0.026). There was no significant difference in operative time and complications between M and C groups (p<0.05). The M group had less mean blood loss than the C group (1275 vs 718mL, p=0.045). Blood transfusion was comparable between the two groups (p<0.05). The mean amount and drainage time were lower than the C group (141 vs 873mL, p<0.001; 3.1 vs 7.0 days, P<0.001). The mean postoperative hospitalization of the M group was 8.8 days, which was lower than the C group (11.3 days, p=0.045). Sub-analysis showed that for patients with hyper-vascular tumor, the M group had less mean amount and time of drainage compared with the C group (p<0.05); for patients with hypo-vascular tumor, the mean blood loss and amount of blood transfusion were also reduced in M group (p<0.05). The mean blood loss and drainage time of patients with hypo-vascular tumors were less than patients with hyper-vascular tumors in the M group (p<0.05). CONCLUSION: In selected cases, minimally invasive tubular surgery is safe and effective for patients with spinal metastasis. Patients with hypo-vascular tumors were more suitable for this technique with less blood loss, fewer blood transfusions, minor drainage, and shorter postoperative hospitalization.
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BACKGROUND: Blood loss in posterior surgery patients with thoracolumbar metastasis posed a significant challenge to surgeons. This study aimed to explore the risk factors of blood loss in posterior surgery for patients with thoracolumbar metastasis. METHODS: One hundred forty-two patients were retrospectively reviewed. Their baseline characteristics were recorded. The Gross equation was used to calculate blood loss on a surgical day. Multivariate linear regression was used to analyze the risk factors. RESULTS: Mean blood loss of 142 patients were 2055 ± 94 ml. Hypervascular primary tumor (kidney, thyroid and liver) (P = 0.017), wide or marginal excision (en-bloc: P = 0.001), metastasis at the lumbar spine (P = 0.033), and the presence of extraosseous tumor mass (P = 0.012) were independent risk factors of blood loss in the posterior surgery. Sub-analysis showed that wide or marginal excision (en-bloc: P < 0.001) and metastasis at lumbar spine (P = 0.007) were associated with blood loss for patients with non-hyper vascular primary tumors. Wide or marginal excision (piece-meal: P = 0.014) and the presence of an extraosseous tumor mass (P = 0.034) were associated with blood loss for patients with hypervascular primary tumors. CONCLUSION: Hypervascular primary tumor (kidney, thyroid, and liver) was an independent risk factor of blood loss in the posterior surgery. The presence of extraosseous tumor mass and wide or marginal excision (piece-meal) were independent risk factors for patients with hypervascular primary tumors. Metastasis at the lumbar spine and wide or marginal excision (en-bloc) were independent risk factors for patients with non-hyper vascular primary tumors.
Subject(s)
Spinal Neoplasms , Humans , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/surgery , Retrospective Studies , Risk Factors , Spinal Neoplasms/diagnostic imaging , Spinal Neoplasms/epidemiology , Spinal Neoplasms/surgery , Treatment OutcomeABSTRACT
BACKGROUND: A retrospective study was performed to summarize the clinicopathological characteristics of breast cancer patients with bone metastasis, to clarify the metastasis sites, and to explore the risk factors affecting prognosis. METHODS: Breast cancer patients with bone metastasis diagnosed in our hospital from January 2008 to January 2019 were included. Through follow-up by telephone call or return visit, the metastasis sites and clinicopathological characteristics were summarized. The risk factors influencing prognosis were analyzed by univariate and multivariate regression analyses. RESULTS: Multifocal bone metastases were dominant in the 150 patients, and the metastatic rates in the spine, chest, pelvis, limbs, and skull were 75.3%, 74.0%, 56.0%, 46.7%, and 28.7%, respectively, with significant differences (P<0.01). Kaplan-Meier univariate analysis showed that age, menstrual status, number of metastatic lymph nodes, clinical stage, endocrine therapy, alkaline phosphatase level, visceral metastasis, and number of bone metastasis sites affected the overall survival. Cox multivariate regression analysis revealed that endocrine therapy, number of metastatic lymph nodes, visceral metastasis, number of bone metastasis sites, and c-erbB-2 expression were independent prognostic factors. CONCLUSIONS: Middle-aged and elderly patients with breast cancer, mainly aged 40-60 years old, are prone to bone metastasis. The incidence rate of bone metastasis is high within 3 years after surgery, involving the spine, chest, pelvis, limbs, and skull in descending order. The number of metastatic lymph nodes, endocrine therapy, visceral metastasis, number of bone metastasis lesions at the first onset, and c-erbB-2 expression are independent prognostic factors influencing the survival rate of breast cancer patients with bone metastasis.
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OBJECTIVE: This study aimed to investigate the effect of timing of surgery on neurological recovery for patients with metastatic spinal cord compression (MSCC). METHODS: According to the timing of surgery, 75 patients with incomplete paraplegia caused by MSCC were assigned to 3 groups: within 3 days (group A), between 4 days and 7 days (group B), and after 7 days (group C). T-test, one-way ANOVA, Mann-Whitney U-test, and Chi-square test were used to evaluate the difference in the improvement of American Spinal Injury Association Impairment Scale (AIS) and ambulatory status, the incidence of perioperative complications, surgical site infection, and the length of hospital stay between 3 groups. RESULTS: Patients with incomplete paraplegia treated in our department had an average of 17.4±1.8 days delayed and most occurred before hospitalization (4.0±0.4 vs 13.2±1.8, P<0.001). There was no significant difference in the AIS improvement between patients with different pre-op AIS. The timing of surgery was significantly correlated with AIS improvement (correlation coefficient=-0.257, P=0.019). Sub-analysis showed that patients who underwent surgery within 7 days (group A and group B) had significantly better AIS improvement compared with group C (improved at least 1 grade, P=0.043; improved more than 1 grade, P=0.039) and the surgery timing was more important for patients with AIS B and C. The timing of surgery was significantly correlated with the length of hospital stay (correlation coefficient=0.335, P=0.003). Patients of group C had the longest length of hospital stay (P=0.002). The incidence of perioperative complications and surgical site infection did not differ significantly between the 3 groups. CONCLUSION: Delay surgery was common in incomplete paraplegia patients with MSCC. Patients with AIS B and C who underwent surgery within 7 days had better AIS improvement.
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Studies have shown that exosomes can mediate the chemoresistance of drug-resistant cells by transmitting circular RNAs (circRNAs). However, the role of exosome-derived hsa_circ_103801 (exosomal hsa_circ_103801) in osteosarcoma (OS) remains unclear. The level of hsa_circ_103801 was upregulated in the serum exosomes from patients with OS, and OS patients with high hsa_circRNA_103801 expression had a shorter survival time relative to patients with low hsa_circ_103801 expression. The expression of hsa_circ_103801 was upregulated in cisplatin-resistant MG63 (MG63/CDDP) cells compared with that in MG63 cells. In addition, hsa_circ_103801 was highly enriched in exosomes derived from CDDP-resistant OS cells and could be delivered to MG63 and U2OS cells through exosomes. Exosomes derived from CDDP-resistant cells were shown to reduce the sensitivity of MG63 and U2OS cells to CDDP, inhibit apoptosis, and increase the expression of multidrug resistance-associated protein 1 and P-glycoprotein. Moreover, exosomal hsa_circ_103801 could strengthen the promotive effect of exosomes on the chemoresistance of MG63 and U2OS cells to CDDP. Hence, serum exosomal hsa_circ_103801 may serve as an effective prognostic biomarker for OS, and exosomal hsa_circ_103801 could be a potential target for overcoming OS chemoresistance.
Subject(s)
Cisplatin/pharmacology , Drug Resistance, Neoplasm , Exosomes , Osteosarcoma , Adult , Cell Line, Tumor , Cell-Free Nucleic Acids/metabolism , Exosomes/drug effects , Exosomes/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Osteosarcoma/drug therapy , Osteosarcoma/metabolism , Young AdultABSTRACT
Various survival scoring systems have been developed to help surgeons select the best candidates for appropriate therapies in patients with metastatic spinal disease. This study aims to discuss the current status and future directions of scoring systems for the prediction of survival prognosis in these patients. The search terms "spine metastases," "metastatic spinal disease," and "metastatic spinal cord compression" were combined with "survival prognosis," "scoring system," and "score" to elicit relevant literatures in PubMed and Embase databases. As a result, 159 articles were selected from PubMed, and 246 articles were extracted from Embase. After reviewing each article, we carefully included and analyzed 74 articles about the development and evaluation of scoring systems for predicting survival prognosis in spine metastases. In this review, those scoring systems were stratified into the historic scoring systems and the modern scoring systems on the basis of the proposed time. The historic scoring systems, including the original/revised Tokuhashi scoring system, the Bauer scoring system, the Tomita scoring system, and the Linden scoring system, and the modern scoring systems, such as the Lei scoring system, the Bartels scoring system, the Mizumoto scoring system, the Bollen scoring system, the Rades scoring system, Oswestry Spinal Risk Index, and the Choi risk calculator, were introduced and discussed in this review. Besides, the clinical effectiveness and pitfalls of the existing systems and the future directions of the next generation of scoring systems were also addressed and discussed. We recommended these scoring systems as preferable reference tools to help doctors to select surgical candidates. In patients with long-term life expectancy, radical surgery, such as wide or marginal excision, can be considered in patients with neurological deficits, spine instability, or severe back pain. Besides, with the advancement and improvement of medical technologies, surgical procedures are changing, which can affect surgical indications such as vertebroplasty, minimal invasive surgery, and percutaneous stabilization, which can also be used in patients with spine instability or severe back pain, and do not require much recovery; hence, they can even be used in patients with relative short-term life expectancy. However, the decision about the treatment of patients with metastatic spinal disease is so complicated and should never rely on prognostic scores alone. The final therapeutic decision should be made by interdisciplinary corporations of oncologists, radiologists, and spinal surgeons. Besides, individual intentions should be respected.
Subject(s)
Prognosis , Spinal Neoplasms/surgery , Disease Progression , Humans , Life Expectancy , Neoplasm Metastasis , Spinal Neoplasms/mortality , Spinal Neoplasms/secondary , Treatment OutcomeABSTRACT
Objective: Inspired by the traditionally clinical application of herb pair Zhimu-Huangbo to treat diabetes, a combination of plant ingredients, timosaponin B2 (TB-2) and berberine (BBR), was evaluated for their anti-diabetic efficacy and cooperative mechanisms. Methods: The efficacy and pharmacokinetics of orally administered TB-2 (33.3 mg/kg/day), BBR (66.7 mg/kg/day), and TB-2+BBR (100 mg/kg/day) were evaluated in spontaneously non-obese diabetic Goto-Kakizaki (GK) rats, and metformin (200 mg/kg/day) was used as a positive control. The comparative exposure of the parent drugs, timosaponin A3 (TB-2 metabolite), and M1-M5 (BBR metabolites) was quantified in the portal vein plasma (before hepatic disposition), liver, and systemic plasma (after hepatic disposition) of normal rats on single and combination treatments. Cooperative mechanism of TB-2 and BBR on intestinal absorption and hepatic metabolism was investigated in Caco-2 cells and primary hepatocytes, respectively. Results: After a 6-week experiment, non-fasting and fasting blood glucose levels and oral glucose tolerance test results showed that TB-2+BBR treatments (100 mg/kg/day) displayed significantly anti-diabetic efficacy in GK rats, comparable to that on metformin treatments. However, no significant improvement was observed on TB-2 or BBR treatments alone. Compared to single treatments, combination treatments led to the increased circulating levels of BBR by 107% in GK rats. In normal rats, the hepatic exposure of BBR, timosaponin A3, and M1-M5 was several hundred folds higher than their circulating levels. Co-administration also improved the levels in the plasma and liver by 41-114% for BBR, 141-230% for TB-2, and 12-282% for M1-M5. In vitro, the interaction between TB-2 and BBR was mediated by intestinal absorption, rather than hepatic metabolism. Conclusion: Combining TB-2 and BBR enhanced the anti-diabetic efficacy by increasing the in vivo variety of effective substances, including the parent compounds and active metabolites, and improving the levels of those substances through intestinal absorption. This study is a new attempt to assess the effects of combined plant ingredients on diabetes by scientifically utilizing clinical experience of an herb pair.
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Methotrexate (MTX) is the gold standard drug for the treatment of rheumatoid arthritis (RA), and it is frequently combined with leflunomide (LEF) to enhance its clinical efficacy. However, this combination can exacerbate liver toxicity, and the underlying mechanism has not yet been clarified. We investigated whether LEF affects the pharmacokinetics of MTX and its primary toxic metabolite, 7-hydroxyl methotrexate (7OH MTX), in mice. LEF significantly increased the plasma concentration (area under the plasma concentration-time curve) of MTX and 7OH MTX (2.4 and 4.5 times, respectively), decreased their bile excretion, and increased their accumulation in the liver and kidneys. When we investigated the effect of LEF on the MTX absorption, distribution, metabolism, and excretion process, we found that LEF had little effect on liver aldehyde oxidase and 7OH MTX formation. However, LEF significantly decreased the expression of the apical efflux transporter multidrug resistance-associated protein 2 (Mrp2) and increased that of the basolateral efflux transporters Mrp3/4, except there was no significant change in Mrp4 protein expression. Mrp2/3/4 alteration changed the distribution of MTX and 7OH MTX in plasma and tissues. Further studies suggested that LEF indirectly activated peroxisome proliferator-activated receptor α (PPARα), which was likely responsible for the Mrp2/3/4 alteration in the liver. The MTX plasma concentration change induced by LEF was reversed by the PPARα-specific antagonist GW6471. These results may partially explain the exacerbated liver toxicity caused by combination treatment with MTX and LEF and may raise concerns regarding the risk of potential drug-drug interactions between PPARα agonists and Mrp substrates in the clinic.
Subject(s)
Leflunomide/metabolism , Liver/metabolism , Methotrexate/analogs & derivatives , Methotrexate/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Animals , Antirheumatic Agents/metabolism , Antirheumatic Agents/pharmacology , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/metabolism , Drug Interactions/physiology , Leflunomide/pharmacology , Male , Methotrexate/pharmacology , Mice , Mice, Inbred C57BL , Oxazoles/pharmacology , PPAR alpha/metabolism , Tyrosine/analogs & derivatives , Tyrosine/pharmacologyABSTRACT
1. Berberine (BBR), an isoquinoline alkaloid, has demonstrated multiple clinical pharmacological actions. As a substrate of multiple transporters in the liver, BBR is rarely excreted into the bile but can be found in the urine. The purpose of the present study was to investigate the role of multidrug and toxin extrusion protein 1 (MATE1) in the transport of BBR in the liver and kidney. 2. Using human MATE1 (hMATE1)-transfected HEK293 cells, BBR was shown to be a substrate of hMATE1 (Km = 4.28 ± 2.18 µM). In primary rat hepatocytes, pH-dependent uptake and efflux studies suggested that the transport of BBR was driven by the exchange of H+ and involved Mate1. In rats, we found that pyrimethamine (PYR), an inhibitor of Mate1, increased hepatic and renal distribution of BBR and decreased systematic excretion of BBR. 3. These findings indicated that BBR is a substrate of MATE1 and that hepatic and renal Mate1 promote excretion of BBR into bile and urine, respectively. In conclusion, Mate1 plays a key role in the distribution and excretion of BBR, and we speculate that drug-drug interactions (DDIs) caused by MATE1 may occur between BBR and other co-administered drugs.
Subject(s)
Berberine/pharmacokinetics , Organic Cation Transport Proteins/metabolism , Animals , Cells, Cultured , Drug Interactions , HEK293 Cells , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Hydrogen-Ion Concentration , Kidney/drug effects , Kidney/metabolism , Male , Metformin/pharmacokinetics , Rats, Sprague-Dawley , Tissue DistributionABSTRACT
Galactose moieties are covalently coupled with sodium alginate to enhance liver-specific functions in microcapsules owing to the specific interaction between the galactose moieties and the asialoglycoprotein receptors (ASGPRs) of hepatocytes. In this study, galactosylated alginate (L-NH2-OH-alginate) based microcapsules with desirable stability and a suitable 3D microenvironment are designed and fabricated for primary hepatocyte applications. The designed L-NH2-OH-alginate is fabricated via the application of ethylenediamine grafted lactobionic acid (L-NH2) onto the hydroxyl groups of sodium alginate so that the negatively charged carboxyl groups intact in L-NH2-OH-alginate can effectively bond with Ca2+ to form a stable three-dimensional gel network; a subsequent reaction with polycations forms a stable membrane of microcapsules. As a result, L-NH2-OH-alginate based microcapsules exhibit an excellent mechanical stability. Moreover, with a higher degree of substitution in L-NH2-OH-alginate (DS 0.41), the hepatocytes entrapped in L-NH2-OH-alginate microcapsules exhibit better viability and well-maintained liver-specific functions.