Chitosan-Linked Dual-Sulfonate COF Nanosheet Proton Exchange Membrane with High Robustness and Conductivity.

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.

Mini-open compared with the trans-tubular approach in patients with spinal metastases underwent decompression surgery---a retrospective cohort study.

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.

Research on Pneumatic Control of a Pressurized Self-Elevating Mat for an Offshore Wind Power Installation Platform.

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.

Micropeptide MIAC inhibits the tumor progression by interacting with AQP2 and inhibiting EREG/EGFR signaling in renal cell carcinoma.

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.

Risk factors for predicting cement leakage in percutaneous vertebroplasty for spinal metastases.

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.

Cisplatin-resistant osteosarcoma cell-derived exosomes confer cisplatin resistance to recipient cells in an exosomal circ_103801-dependent manner.

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.

Risk factors of total blood loss in the posterior surgery for patients with thoracolumbar metastasis.

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.

Leflunomide Increases Hepatic Exposure to Methotrexate and Its Metabolite by Differentially Regulating Multidrug Resistance-Associated Protein Mrp2/3/4 Transporters via Peroxisome Proliferator-Activated Receptor α Activation.

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.

The involvement of multidrug and toxin extrusion protein 1 in the distribution and excretion of berberine.

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.

Hepatocellular carcinoma repression by TNFα-mediated synergistic lethal effect of mitosis defect-induced senescence and cell death sensitization.

UNLABELLED: Hepatocellular carcinoma (HCC) is a cancer lacking effective therapies. Several measures have been proposed to treat HCCs, such as senescence induction, mitotic inhibition, and cell death promotion. However, data from other cancers suggest that single use of these approaches may not be effective. Here, by genetic targeting of Survivin, an inhibitor of apoptosis protein (IAP) that plays dual roles in mitosis and cell survival, we identified a tumor necrosis factor alpha (TNFα)-mediated synergistic lethal effect between senescence and apoptosis sensitization in malignant HCCs. Survivin deficiency results in mitosis defect-associated senescence in HCC cells, which triggers local inflammation and increased TNFα. Survivin inactivation also sensitizes HCC cells to TNFα-triggered cell death, which leads to marked HCC regression. Based on these findings, we designed a combination treatment using mitosis inhibitor and proapoptosis compounds. This treatment recapitulates the therapeutic effect of Survivin deletion and effectively eliminates HCCs, thus representing a potential strategy for HCC therapy. CONCLUSION: Survivin ablation dramatically suppresses human and mouse HCCs by triggering senescence-associated TNFα and sensitizing HCC cells to TNFα-induced cell death. Combined use of mitotic inhibitor and second mitochondrial-derived activator of caspases mimetic can induce senescence-associated TNFα and enhance TNFα-induced cell death and synergistically eliminate HCC. (Hepatology 2016;64:1105-1120).

Systematic and comprehensive strategy for metabolite profiling in bioanalysis using software-assisted HPLC-Q-TOF: magnoflorine as an example.

Metabolite profiling plays a crucial role in drug discovery and development, and HPLC-Q-TOF has evolved into a powerful and effective high-resolution analytical tool for metabolite detection. However, traditional empirical identification is laborious and incomplete. This paper presents a systematic and comprehensive strategy for elucidating metabolite structures using software-assisted HPLC-Q-TOF that takes full advantage of data acquisition, data processing, and data mining technologies, especially for high-throughput metabolite screening. This strategy has been successfully applied in the study of magnoflorine metabolism based on our previous report of its poor bioavailability and drug-drug interactions. In this report, 23 metabolites of magnoflorine were tentatively identified with detailed fragmentation pathways in rat biological samples (urine, feces, plasma, and various organs) after i.p. or i.g. administration, and for most of these metabolites, the metabolic sites were determined. The phase I biotransformations of magnoflorine (M1-M7, M10-M14) consist of demethylation, dehydrogenation, hydroxylation, methylene to ketone transformation, N-ring opening, and dehydroxylation. The phase II biotransformations (M8, M9, and M15-M23) consist of methylation, acetylation, glucuronidation, and N-acetylcysteine conjugation. The results indicate that the extensive metabolism and wide tissue distribution of magnoflorine and its metabolites may partly contribute to its poor bioavailability and drug-drug interaction, and i.p. administration should thus be a suitable approach for isolating magnoflorine metabolites. In summary, this strategy could provide an efficient, rapid, and reliable method for the structural characterization of drug metabolites and may be applicable for general Q-TOF users.

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity.

AIM: Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo. METHODS: The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro. Hepatic cytochrome P450 reductase null (HRN) mice were used to examine the PK profiling and hepatotoxicity of leflunomide in vivo. The expression and function of sodium/bile acid cotransporter (NTCP) were assessed in rat and human hepatocytes and NTCP-transfected HEK293 cells. After Male Sprague-Dawley (SD) rats were administered teriflunomide (1,6, 12 mg · kg(-1) · d(-1), ig) for 4 weeks, their blood samples were analyzed. RESULTS: A nonspecific CYPs inhibitor aminobenzotriazole (ABT, 1 mmol/L) decreased the IC50 value of leflunomide in rat hepatocytes from 409 to 216 µmol/L, whereas another nonspecific CYPs inhibitor proadifen (SKF, 30 µmol/L) increased the cellular accumulation of leflunomide to 3.68-fold at 4 h. After oral dosing (15 mg/kg), the plasma exposure (AUC0-t) of leflunomide increased to 3-fold in HRN mice compared with wild type mice. Administration of leflunomide (25 mg·kg(-1) · d(-1)) for 7 d significantly increased serum ALT and AST levels in HRN mice; when the dose was increased to 50 mg·kg(-1) · d(-1), all HRN mice died on d 6. Teriflunomide significantly decreased the expression of NTCP in human hepatocytes, as well as the function of NTCP in rat hepatocytes and NTCP-transfected HEK293 cells. Four-week administration of teriflunomide significantly increased serum total bilirubin and direct bilirubin levels in female rats, but not in male rats. CONCLUSION: Hepatic CYPs play a critical role in detoxification process of leflunomide, whereas the major metabolite teriflunomide suppresses the expression and function of NTCP, leading to potential cholestasis.

Improving the dissolution and bioavailability of 6-mercaptopurine via co-crystallization with isonicotinamide.

6-Mercaptopurine (6-MP) is a clinically important antitumor drug. The commercially available form was provided as monohydrate and belongs to BCS class II category. Co-crystallization screening by reaction crystallization method (RCM) and monitored by powder X-ray diffraction led to the discovery of a new co-crystal formed between 6-MP and isonicotinamide (co-crystal 1). Co-crystal 1 was thoroughly characterized by X-ray diffraction, FT-IR and Raman spectroscopy, and thermal analysis. Noticeably, the in vitro and in vivo studies revealed that co-crystal 1 possesses improved dissolution rate and superior bioavailability on animal model.

Organic anion-transporting polypeptides contribute to the hepatic uptake of berberine.

1. The purpose of this study was to investigate the mechanism of hepatic uptake of berberine. Berberine accumulation in hepatocytes was found to be highly dependent on active uptake, which could not be explained by liver organic cation transporter (OCT) alone. 2. Our studies indicated that berberine uptake was significantly suppressed by rifampicin, cyclosporine A and glycyrrhizic acid, which act as specific inhibitors of different Oatp isoforms (Oatp1a1, Oatp1a4 and Oatp1b2) in rat hepatocytes. The combination of OCT and OATP inhibitors further reduced berberine accumulation in both rat and human hepatocytes. The uptake of berberine could be increased in human HEK293-OATP1B3 but not in OATP1B1-transfected HEK 293 cells. 3. Rifampicin could reduce the berberine liver extraction ratio (ER) and double its concentration in the effluent in isolated rat livers. Further in vivo study indicated that berberine plasma exposure could be significantly increased by co-administration of the OATP inhibitor rifampicin or the substrate rosuvastatin. 4. In conclusion, this study demonstrated that both OCT and OATP contribute to the accumulation of berberine in the liver. OATPs may have important roles in berberine liver disposition and potential clinically relevant drug--drug interactions.

Study on the PK profiles of magnoflorine and its potential interaction in Cortex phellodendri decoction by LC-MS/MS.

Magnoflorine, an aporphine alkaloid in Cortex phellodendri, is increasingly attracting research attention because of its antidiabetic effects. However, at present, little information on its pharmacokinetics (PK) in vivo is available. In this study, a sensitive, rapid, and selective method was developed to determine the magnoflorine content in rat plasma using liquid chromatography-tandem mass spectrometry. Following liquid-liquid extraction, the calibration curve showed good linearity within the concentration range of 2.93 to 1,500 ng ml(-1). The intra- and inter-day precisions were all below 7.8 %, and the accuracy ranged from 94.9 to 103.4 %. The method was successfully applied in investigating the PK of magnoflorine in rats. The compound had low bioavailability, a high absorption rate, and a high elimination rate. However, area under the curve, T 1/2, and MRT increased approximately twofold when the same dosage of the compound was administered in a C. phellodendri decoction (20.8 g kg(-1)). Moreover, T max was prolonged from 0.3 to 3.33 h. Furthermore, a comparison of coadministration of the mixture group, magnoflorine (40 mg kg(-1)) and berberine (696.4 mg kg(-1)), with the C. phellodendri decoction group, revealed that no statistical difference (P > 0.05) was found in the parameter AUC, and certain similar changes in the PK trend to the herbal medicine group were also observed. These results suggested that oral administration of the herbal medicine decreased the absorption and elimination rates of magnoflorine and increased its bioavailability. Berberine played a significant role in interacting with magnoflorine and in affecting the PK profiles of magnoflorine in the C. phellodendri decoction group.

Pharmacokinetics, pharmacodynamics, and safety of frunexian in healthy Chinese volunteer adults: A randomized dose-escalation phase I study.

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.

Manual Homogenization Improves the Sensitivity of Microbiological Culture for Patients with Pyogenic Spondylitis.

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.

Flat dose regimen of toripalimab based on model-informed drug development approach.

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.

Clinicopathological characteristics and prognostic risk factors of breast cancer patients with bone metastasis.

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.

Effect of the Timing of Surgery on Neurological Recovery for Patients with Incomplete Paraplegia Caused by Metastatic Spinal Cord Compression.

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.