CCL2 promotes EGFR-TKIs resistance in non-small cell lung cancer via the AKT-EMT pathway.

Acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) represents a primary cause of treatment failure in non-small cell lung cancer (NSCLC) patients. Chemokine (C-C motif) ligand 2 (CCL2) is recently found to play a pivotal role in determining anti-cancer treatment response. However, the role and mechanism of CCL2 in the development of EGFR-TKIs resistance have not been fully elucidated. In the present study, we focus on the function of CCL2 in the development of acquired resistance to EGFR-TKIs in NSCLC cells. Our results show that CCL2 is aberrantly upregulated in EGFR-TKIs-resistant NSCLC cells and that CCL2 overexpression significantly diminishes sensitivity to EGFR-TKIs. Conversely, CCL2 suppression by CCL2 synthesis inhibitor, bindarit, or CCL2 knockdown can reverse this resistance. CCL2 upregulation can also lead to enhanced migration and increased expressions of epithelial-mesenchymal transition (EMT) markers in EGFR-TKI-resistant NSCLC cells, which could also be rescued by CCL2 knockdown or inhibition. Furthermore, our findings suggest that CCL2-dependent EGFR-TKIs resistance involves the AKT-EMT signaling pathway; inhibition of this pathway effectively attenuates CCL2-induced cell migration and EMT marker expression. In summary, CCL2 promotes the development of acquired EGFR-TKIs resistance and EMT while activating AKT signaling in NSCLC. These insights suggest a promising avenue for the development of CCL2-targeted therapies that prevent EGFR-TKIs resistance in NSCLC.

Tripartite motif-containing protein 26 promotes colorectal cancer growth by inactivating p53.

Tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase that exhibits divergent roles in various cancer types (oncogenic and anti-oncogenic). This study investigates the interaction of TRIM26 with the tumor suppressor protein p53 in colorectal cancer (CRC) cells by performing a comprehensive set of biochemical, cell-based assays, and xenograft experiments. As a result, we found that overexpression of TRIM26 significantly enhances CRC cell proliferation and colony formation, while knockdown of TRIM26 suppresses these processes. Xenograft experiments further validated the tumor-promoting role of TRIM26 in CRC. Supporting this is that TRIM26 is highly expressed in human CRC tissues as revealed by our analysis of the TCGA database. Biochemically, TRIM26 directly bound to the C-terminus of p53 and facilitated its ubiquitination, resulting in proteolytic degradation and attenuated p53 activity independently of MDM2. Also, TRIM26 increased the MDM2-mediated ubiquitination of p53 by binding to MDM2's C-terminus. This study uncovers the oncogenic potential of TRIM26 in CRC by inhibiting p53 function. Through its ubiquitin ligase activity, TRIM26 destabilizes p53, consequently promoting CRC cell proliferation and tumor growth. These findings shed light on the complex involvement of TRIM26 in cancer and identify this ubiquitin ligase as a potential therapeutic target for future development of CRC treatment.

iTTCA-MVL: A multi-view learning model based on physicochemical information and sequence statistical information for tumor T cell antigens identification.

Immunotherapy is an emerging treatment method aimed at activating the human immune system and relying on its own immune function to kill cancer cells and tumor tissues. It has the advantages of wide applicability and minimal side effects. Effective identification of tumor T cell antigens (TTCAs) will help researchers understand their functions and mechanisms and carry out research on anti-tumor vaccine development. Considering that using biological experimental technology to identify TTCAs can be costly and time-consuming, it is necessary to develop a robust bioinformatics computing tool. At present, different machine learning models have been proposed for identifying TTCAs, but there is still room for further improvement in their performance. To establish a TTCA predictor with better prediction performance, we propose a prediction model called iTTCA-MVL in this paper. We extracted three sets of features from the views of physicochemical information and sequence statistics, namely the distribution descriptor of composition, transition, and distribution (CTDD), TF-IDF, and LSA topic. Then, we used least squares support vector machines (LSSVMs) as submodels and Hilbert‒Schmidt independence criteria (HSIC) as constraints to establish an independent and complementary multi-view learning model. The prediction accuracy of iTTCA-MVL on the independent test set is 0.873, and Matthew's correlation coefficient is 0.747, which is significantly better than those of existing methods. Therefore, iTTCA-MVL is an excellent prediction tool that researchers can use to accurately identify TTCAs.

Comparison of robotic-assisted versus conventional laparoscopic surgery in colorectal cancer resection: a systemic review and meta-analysis of randomized controlled trials.

Introduction: There is still controversy on whether or not robot-assisted colorectal surgery (RACS) have advantages over laparoscopic-assisted colorectal surgery(LACS). Materials and methods: The four databases (PubMed, Embase, Web of Science and Cochrane Library)were comprehensively searched for randomized controlled trials (RCTs) comparing the outcomes of RACS and LACS in the treatment of colorectal cancer from inception to 22 July 2023. Results: Eleven RCTs were considered eligible for the meta-analysis. Compared with LACS,RACS has significantly longer operation time(MD=5.19,95%CI: 18.00,39.82, P<0.00001), but shorter hospital stay(MD=2.97,95%CI:-1.60,-0.33,P = 0.003),lower conversion rate(RR=3.62,95%CI:0.40,0.76,P = 0.0003), lower complication rate(RR=3.31,95%CI:0.64,0.89,P=0.0009),fewer blood loss(MD=2.71,95%CI:-33.24,-5.35,P = 0.007),lower reoperation rate(RR=2.12, 95%CI:0.33,0.96,P=0.03)and longer distal resection margin(MD=2.16, 95%CI:0.04,0.94, P = 0.03). There was no significantly difference in harvested lymph nodes, the time of first flatus, the time of first defecation,the time of first resume diet, proximal resection margin, readmission rates, mortalities and CRM+ rates between two group. Conclusions: Our study indicated that RACS is a feasible and safe technique that can achieve better surgical efficacy compared with LACS in terms of short-term outcomes. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023447088.

Comparison of robot-assisted thoracic surgery versus video-assisted thoracic surgery in the treatment of lung cancer: a systematic review and meta-analysis of prospective studies.

Introduction: Previous studies have compared robot-assisted thoracic surgery(RATS) with video-assisted thoracic surgery (VATS) in the treatment of patients with lung cancer, but results were conflicting. The present meta-analysis aimed to compare the clinical outcomes of RATS with VATS in the treatment of patients with lung cancer. Materials and methods: Web of Science, PubMed, Cochrane Library and Embase were comprehensively searched for randomized controlled trials or prospective cohort studies comparing the clinical outcomes of RATS and VATS from inception to 22 July 2023. The Cochrane Risk of Bias tool was used to assess risk of bias. Meta-analyses of length of hospital stay, postoperative duration of drainage, postoperative complications, operative time, conversion, estimated blood loss, the number of dissected lymph nodes and stations, 30-day readmission and 30-day mortality were performed. Results: In total 5 studies were included in the meta-analysis. A total of 614 patients were included, of which 299 patients were treated by RATS and 315 patients treated by VATS. Blood loss was significantly less in RATS group than that in VATS (MD = -17.14, 95% CI -29.96 ~ -4.33, P = 0.009). More nodes stations were dissected in RATS group compared with VATS group(MD= 1.07, 95% CI 0.79 ~ 1.36, P < 0.001). No significant difference occurred between RATS and VATS in length of hospital stay(MD= -0.19, 95% CI -0.98~0.61), readmission(OR=0.74, 95%CI 0.36~1.51, P=0.41), operative time(MD=11.43 95% CI -8.41~31.26, P=0.26), conversion(OR=0.58, 95% CI 0.29~1.17, P=0.13), number of dissected lymph nodes(MD=0.98, 95% CI -0.02~1.97, P=0.05), upstaging rate(OR =0.67, 95% CI 0.38 ~ 1.18, P =0.16, I2 = 0%), time of chest tube drainage (MD= -0.34, 95%CI -0.84~0.15, P=0.17), post-operative complications(OR=0.76, 95% CI 0.52~ 1.11, P=0.16) and total cost(MD = 3103.48, 95% CI -575.78 ~ 6782.74, P=0.1, I2 = 99%). Conclusion: RATS is a feasible and safe treatment that can achieve better surgical outcomes compared with VATS in terms of short-term outcomes. Except of higher total cost, RATS has obvious advantage in lymphadenectomy and control of intraoperative bleeding. However, large sample and long follow-up randomized clinical trials comparing RATS with VATS are still necessary to better demonstrate the advantages of RATS for lung cancer. Systematic review registration: https://www.crd.york.ac.uk/prospero/, Identifier CRD42023446653.

Prediction of thermophilic protein using 2-D general series correlation pseudo amino acid features.

The demand for thermophilic protein has been increasing in protein engineering recently. Many machine-learning methods for identifying thermophilic proteins have emerged during this period. However, most machine learning-based thermophilic protein identification studies have only focused on accuracy. The relationship between the features' meaning and the proteins' physicochemical properties has yet to be studied in depth. In this article, we focused on the relationship between the features and the thermal stability of thermophilic proteins. This method used 2-D general series correlation pseudo amino acid (SC-PseAAC-General) features and realized accuracy of 82.76% using the J48 classifier. In addition, this research found the presence of higher frequencies of glutamic acid in thermophilic proteins, which help thermophilic proteins maintain their thermal stability by forming hydrogen bonds and salt bridges that prevent denaturation at high temperatures.

Efficacy and safety of neoadjuvant PD-1 inhibitors or PD-L1 inhibitors for muscle invasive bladder cancer: a systematic review and meta-analysis.

Introduction: This meta-analysis aims to evaluate the efficacy and safety of neoadjuvant PD-1 inhibitors or PD-L1 inhibitors [PD-(L)1 inhibitors] for muscle-invasive bladder carcinoma (MIBC). Materials and methods: Four databases (Medline, Embase, Web of Science, and 21 CENTRAL) were searched for articles studying neoadjuvant PD-(L)1 inhibitors for MIBC. The search time period was from the establishment of each database to 21 July 2023. Meta-analyses of pCR, pPR, Grade≥ 3 irAEs rate, RFS, and OS were performed. Results: In total, 22 studies were included for meta-analysis. The overall pooled pCR of neoadjuvant PD-(L)1 inhibitors was 0.36 (95%CI=0.30-0.42, p=0.00). In subgroup meta-analysis, the pooled PCR of PD-(L)1 inhibitors alone, PD-(L)1 inhibitors plus other ICI, and PD-(L)1 inhibitors plus chemotherapy was 0.27 (95%CI=0.19-0.35, p=0.1), 0.41 (95%CI=0.21-0.62, p=0.01), 0.43 (95%CI=0.35-0.50, p=0.06), respectively. The overall pooled pPR of neoadjuvant PD-(L)1 inhibitors was 0.53 (95%CI=0.46-0.60, p=0.00). In subgroup meta-analysis, the pooled pPR of PD-(L)1 inhibitors alone, PD-(L)1 inhibitors plus other ICI, and PD-(L)1 inhibitors plus chemotherapy was 0.36 (95%CI=0.22-0.51, p=0.01), 0.51 (95%CI=0.39-0.62, p=0.43), and 0.61 (95%CI=0.53-0.69, p=0.01), respectively. Kaplan-Meier curves for OS and RFS were reconstructed, but there was no significant difference among three groups in terms of OS or RFS. The pooled result of Grade≥ 3 irAEs rate for neoadjuvant PD-(L)1 inhibitors was 0.15 (95%CI=0.09-0.22, p=0.00%). In subgroup analysis, the pooled result of Grade≥ 3 irAEs rate for PD-(L)1 inhibitors alone, PD-(L)1 inhibitors plus other ICI, and PD-(L)1 inhibitors plus chemotherapy was 0.07 (95%CI=0.04-0.11, p=0.84), 0.31 (95%CI=0.16-0.47, p=0.06), and 0.17 (95%CI=0.06-0.31, I2 = 71.27%, p=0.01), respectively. Conclusion: Neoadjuvant PD-(L)1 inhibitors were feasible and safe for muscle invasive bladder cancer. Compared with PD-(L)1 inhibitors alone, PD-(L)1 inhibitors plus other ICI and PD-(L)1 inhibitors plus chemotherapy were associated with higher pCR and pPR, but higher Grade≥3 irAEs. Kaplan-Meier curves for OS and RFS indicated that neoadjuvant PD-(L)1 inhibitors had an acceptable long-term prognostic, but it was not possible to discern statistical differences between the three neoadjuvant subgroups. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023452437, identifier PROSPERO (CRD42023452437).

Evaluation of the performance of Ca-deficient hydroxyapatite (CDHA)/MgF2 bilayer coating on biodegradable high-purity magnesium in a femoral condyle defect model in rabbits.

The two most critical factors in promoting the clinical translation of magnesium (Mg) are reducing its degradation rate and improving its osteogenesis. In this study, a Ca-deficient hydroxyapatite (CDHA)/MgF2 bilayer coating was prepared on high-purity magnesium (HP Mg) rods by fluorination and hydrothermal treatment. Scanning electron microscope showed that the thickness of the bilayer coating was 3.78 µm and that the surface morphology was nanoscale. In an in vivo experiment on femoral condyle defects in rabbits, the serum magnesium ion levels of rabbits were always in the normal range after surgery, and the liver and kidney functions were not abnormal, which indicated that the CDHA/MgF2 bilayer coating has good biosafety. Micro-CT showed that the CDHA/MgF2 bilayer coating significantly reduced the degradation rate of the HP Mg rods and enhanced the promotion of bone formation. Hard tissue sections showed that the CDHA/MgF2 bilayer coating gave the bone tissue a tight contact interface with the HP Mg rod and improved the bone mass. Immunohistochemistry showed that the expression of vascular endothelial growth factor and BMP-2 was more obvious. These results confirm that the CDHA/MgF2 bilayer coating can improve the properties of HP Mg and provide a basis for the further transformation of HP Mg in the future. It also provides a new reference for the surface modification of magnesium metal.

CC Chemokine Ligand-2: A Promising Target for Overcoming Anticancer Drug Resistance.

CC chemokine ligand-2 (CCL2), a proinflammatory chemokine that mediates chemotaxis of multiple immune cells, plays a crucial role in the tumor microenvironment (TME) and promotes tumorigenesis and development. Recently, accumulating evidence has indicated that CCL2 contributes to the development of drug resistance to a broad spectrum of anticancer agents, including chemotherapy, hormone therapy, targeted therapy, and immunotherapy. It has been reported that CCL2 can reduce tumor sensitivity to drugs by inhibiting drug-induced apoptosis, antiangiogenesis, and antitumor immunity. In this review, we mainly focus on elucidating the relationship between CCL2 and resistance as well as the underlying mechanisms. A comprehensive understanding of the role and mechanism of CCL2 in anticancer drug resistance may provide new therapeutic targets for reversing cancer resistance.

Cancer-derived C-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart.

The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert 'dominant-negative' effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus (p53 long C-terminus, p53LC) in a variety of human cancers. Interestingly, the two representative mutants (named 'p53-374*48' and 'p53-393*78') as tested in this study show both loss-of-function and dominant-negative phenotypes in cell proliferation and colony formation assays. Mechanistically, p53LCs interact with and retain wt p53 in the cytoplasm and prevent it from binding to the promoters of target genes, consequently inhibiting its transcriptional activity. Also, p53LCs are very stable, though not acetylated in cells. Remarkably, the p53LCs can desensitize wt p53-containing cancer cells to p53-activating agents. Together, our results unveil a longer form of p53 mutant that possesses a dominant-negative effect on its wt counterpart, besides losing its wt activity.

Inactivating p53 is essential for nerve growth factor receptor to promote melanoma-initiating cell-stemmed tumorigenesis.

Nerve growth factor receptor (NGFR, CD271, or p75NTR) is highly expressed in melanoma-initiating cells (MICs) and is critical for their proliferation and tumorigenesis, and yet the underlying mechanism(s) remain incompletely understood. We previously showed that NGFR inhibits p53 activity in a negative feedback manner in various cancer cells. Here we report that this feedback inhibition of p53 by NGFR plays an essential role in maintaining the sphere formation (stem-like phenotype) and proliferation of MICs, and in promoting MIC-derived melanoma growth in vivo. Knockdown of NGFR markedly reduced the size and number of spheroid formation of melanoma cells, which can be rescued by ectopically expressed NGFR. This reduction was also reversed by depleting p53. Consistently, knockdown of NGFR led to the suppression of MIC-derived xenograft tumor growth by inducing the p53 pathway. These results demonstrate that the NGFR-p53 feedback loop is essential for maintaining MIC stem-like phenotype and MIC-derived tumorigenesis, and further validates NGFR as a potential target for developing a molecule-based therapy against melanoma.

REG γ knockdown suppresses proliferation by inducing apoptosis and cell cycle arrest in osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most common malignant bone tumor with high mortality in children and adolescents. REG γ is overexpressed and plays oncogenic roles in various types of human cancers. However, the expression and potential roles of REG γ in osteosarcoma are elusive. This study aims at exploring possible biological functions of REG γ in the pathogenesis of osteosarcoma and its underlying mechanism. METHODS: Quantitativereverse transcription-polymerase chain reaction (qRT-PCR), western blotting andimmunohistochemistry (IHC)were performed to detect the expression levels of REG γ in OS tissues and cell lines. Then, the effects of REG γ expression on OS cell proliferation in vitro were analyzed by Cell Counting Kit-8 (CCK-8), ethylene deoxyuridine (EdU), colony formation, flow cytometry. The protein levels of apoptosis and cell-cycle related proteins were evaluated using western blotting. RESULTS: In present study, we found for the first time that REG γ is overexpressed in osteosarcoma tissues and cell lines and knockdown of REG γ significantly inhibits cell proliferation and induces apoptosis and cell cycle arrest in osteosarcoma cells. Furthermore, we observed that p21, caspase-3 and cleaved caspase-3 are increased while the expression of cycinD1 and bcl-2 are decreased after REG γ depletion in osteosarcoma cells. In conclusion, REG γ may be involved in the proliferation of osteosarcoma and serve as a novel therapeutic target in patients with osteosarcoma.

Berberine Promotes OATP1B1 Expression and Rosuvastatin Uptake by Inducing Nuclear Translocation of FXR and LXRα.

Berberine, a quinoline alkaloid, can be used in combination with statins to enhance hypolipidemic effects and reduce the dose and side effects of statins. The hypolipidemic effects of statins in the liver are mainly regulated by organic anion transporting polypeptides (OATPs), and the expression of OATPs is regulated by nuclear receptors. Berberine has been reported to affect nuclear receptors. However, whether berberine affects the uptake of statins by regulating nuclear receptor-mediated expression of OATPs remains to be determined. The aim of this study was to investigate the effects of berberine on the expression of OATP1B1 in HepG2 and explore the underlying mechanism. In HepG2 cells, 10-50 µM berberine significantly increased the uptake of rosuvastatin by inducing the expression of OATP1B1 mRNA and protein. Dual-Luciferase reporter assay showed that luciferase activity of hFXR and hLXRα activated OATP1B1 promoter was increased by 2.5-50 µM berberine in a concentration-dependent manner, with half-maximal effective concentration (EC50) of 12.19 ± 0.86 and 32.15 ± 2.32 µM, respectively. In addition, after silencing FXR or LXRα by small interfering RNA (siRNA), berberine-induced OATP1B1 expression was significantly attenuated. Western blot analysis of FXR and LXRα protein levels in the cytoplasm and nucleus of HepG2 cells after treatment with berberine showed that berberine induced nuclear translocation and activation of FXR and LXRα. In conclusion, berberine-induced nuclear translocation of FXR and LXRα could activate OATP1B1 promoter, resulting in enhanced expression of OATP1B1 and increased uptake of rosuvastatin.

Structural characterization of a safflower polysaccharide and its promotion effect on steroid-induced osteonecrosis in vivo.

A water-soluble polysaccharide (SPAW) was purified from Safflower and it was identified to be (1→3)-linked ß-d-Glucan. The therapeutic effect and underlying mechanism of SPAW on steroid-induced avascular necrosis of the femoral head (SANFH) in a rabbit model was performed here. The abnormal histopathologic changes and apoptosis of femoral head in model group were significantly reverted after SPAW (25, 100 and 200 mg/kg) administration for 60 days, as evidenced by the a decline of empty lacunae rate, the average bone marrow fat cell size and the proportion of apoptotic cells. Furthermore, administration of SPAW significantly decreased the Bax and caspase-3 protein expression, but increased the protein expression of Bcl-2 when compared these in model rabbits. Meanwhile, increased hydroxyproline (HOP) and decreased serum hexosamine (HOM) concentration in rabbit serum were turned to the opposite way. The present study suggested that SPAW may provide an alternative treatment for the treatment of SANFH.

High-purity weight-bearing magnesium screw: Translational application in the healing of femoral neck fracture.

Magnesium (Mg)-based metals can be used as next-generation fracture internal fixation devices due to their specific properties. We used vascularized bone grafting fixed by degradable pure Mg screws and obtained satisfactory results in the treatment of osteonecrosis of the femoral head. However, the mechanical properties of these screws make them weaker than those made of traditional metals. In particular, one of the main challenges of using screws made of Mg-based metals is their application in fixation at important weight-bearing sites in the human body. Femoral neck fracture is a common clinical injury. In this injury, the large bearing stress at the junction requires a fixation device with extremely high mechanical strength. Surgery and appropriate internal fixation can accelerate the healing of femoral neck fractures. Traditional internal fixation devices have some disadvantages after surgery, including stress shielding effects and the need for secondary surgery to remove screws. On the basis of previous work, we developed high-strength pure Mg screws for femoral neck fractures. In this study, we describe the first use of high-purity Mg to prepare large-size weight-bearing screws for the fixation of femoral neck fractures in goats. We then performed a 48 weeks follow-up study using in vivo transformation experiments. The results show that these biodegradable high-purity Mg weight-bearing screws had sufficient mechanical strength and a degradation rate compatible with bone repair. Furthermore, good bone formation was achieved during the degradation process and reconstruction of the bone tissue and blood supply of the femoral head and femoral neck. This study provides a basis for future research on the clinical transformation of biodegradable high-purity Mg weight-bearing screws.

The backward traction test: a new and effective test for diagnosis of biceps and pulley lesions.

BACKGROUND: The value of physical examination for diagnosis of lesions of the long head of the biceps (LHB) and the pulley remains unsatisfactory. The purpose of this study was to describe a new diagnostic test, the backward traction (BT) test, to detect lesions of the LHB and the biceps pulley. METHODS: A prospective study of 143 patients was performed to evaluate the diagnostic value of the BT test and 2 traditional clinical tests (Speed and Yergason tests). Shoulder arthroscopy was used as the "gold standard." RESULTS: For the detection of LHB injury, the BT test was the most sensitive (74%) and accurate (68%). The BT test had a higher diagnostic value for pulley lesions, with a high sensitivity of 81% and an accuracy of 71%. No significant differences in terms of specificity for LHB and pulley lesions were observed between tests. Regarding pulley lesions, the internally rotated and externally rotated BT test positions had high specificity for the diagnosis of specific anteromedial and posterolateral pulley lesions (79% and 73%, respectively). The BT test had a high κ coefficient of 0.768-0.811. CONCLUSION: The BT test is more sensitive and accurate as a new test for LHB and pulley lesions and also specific to distinguish the medial sling and lateral sling lesions of the pulley.

The Emerging Role of the SLCO1B3 Protein in Cancer Resistance.

Currently, chemotherapy is one of the mainstays of oncologic therapies. But the efficacy of chemotherapy is often limited by drug resistance and severe side effects. Consequently, it is becoming increasingly important to investigate the underlying mechanism and overcome the problem of anticancer chemotherapy resistance. The solute carrier organic anion transporter family member 1B3 (SLCO1B3), a functional transporter normally expressed in the liver, transports a variety of endogenous and exogenous compounds, including hormones and their conjugates as well as some anticancer drugs. The extrahepatic expression of SLCO1B3 has been detected in different cancer cell lines and cancer tissues. Recently, accumulating data indicates that the abnormal expression and function of SLCO1B3 are involved in resistance to anticancer drugs, such as taxanes, camptothecin and its analogs, SN-38, and Androgen Deprivation Therapy (ADT) in breast, prostate, lung, hepatic, and colorectal cancer, respectively. Thus, more investigations have been implemented to identify the potential SLCO1B3-related mechanisms of cancer drug resistance. In this review, we focus on the emerging roles of SLCO1B3 protein in the development of cancer chemotherapy resistance and briefly discuss the mechanisms of resistance. Elucidating the function of SLCO1B3 in chemoresistance may bring out novel therapeutic strategies for cancer treatment.

Pharmacokinetic analysis of plasma bicyclol by liquid chromatography-tandem mass spectrometry.

Bicyclol is a synthetic drug widely used to treat chronic hepatitis B. This study aimed to develop a selective, sensitive and high-throughput liquid chromatography-tandem mass spectrometric method for the detection of bicyclol in human plasma. Bicyclol was detected using a multiple reaction monitoring mode, with ammonium adduct ions (m/z 408.2) as the precursor ion and the [M-CH3 ]+ ion (m/z 373.1) subjected to demethylation as the product ion. Chromatographic separation was achieved using a Zobax Eclipse XDB-C18 column with a gradient elution and a mobile phase of 2 mm ammonium formate and acetonitrile. Bicyclol was extracted from plasma matrix by precipitation. A linear detection response was obtained for bicyclol ranging from 0.500 to 240 ng/mL, and the lower limit of quantification was 0.500 ng/mL. The intra- and inter-day precisions were all ≤7.4%, and the accuracies were within ±6.0%. The extraction recovery was >95.9%, and the matrix effects were between 96.0% and 108%. Bicyclol was found to be unstable in human plasma at room temperature, but the degradation was minimized by conducting sample collection and preparation in an ice bath. The validated method was successfully applied to investigate the pharmacokinetics of bicyclol tablets in six healthy Chinese volunteers.

Elevated levels of interleukin-1ß, interleukin-6, tumor necrosis factor-α and vascular endothelial growth factor in patients with knee articular cartilage injury.

BACKGROUND: Inflammatory cytokines play a vital role in the occurrence of osteoarticular injury and inflammation. Whether inflammation-associated factors interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) are involved in the pathogenesis of keen articular cartilage injury remains poorly understood. AIM: To measure the levels of inflammatory factors [IL-1ß, IL-6, TNF-α and VEGF] in patients with knee articular cartilage injury. METHODS: Fifty-five patients with knee articular cartilage injury were selected as patient groups, who were divided into three grades [mild (n = 20), moderate (n = 19) and severe (n = 16)] according to disease severity and X-ray examinations. Meanwhile, 30 healthy individuals who underwent physical examination were selected as the control group. The levels of IL-1ß, IL-6, TNF-α and VEGF were measured by ELISA and immunohistochemical staining. RESULTS: Compared with the control group, patient groups displayed significantly higher levels of IL-1ß, IL-6, TNF-α and VEGF, and the extent of increase was directly proportional to the severity of injury (P < 0.05). In addition, the number of cells with positive staining of IL-1ß, IL-6, TNF-α and VEGF in the synovial membrane were significantly increased, along with increased disease severity (P < 0.05). After treatment, the scores of visual analogue scale and the Western Ontario and McMaster University of Orthopaedic Index in patient groups were 2.26 ± 1.13 and 15.56 ± 7.12 points, respectively, which were significantly lower than those before treatment (6.98 ± 1.32 and 49.48 ± 8.96). Correlation analysis suggested that IL-1ß and TNF-α were positively correlated with VEGF. CONCLUSION: IL-1ß, IL-6, TNF-α and VEGF levels are increased in patients with knee articular cartilage injury, and are associated with the disease severity, indicating they might play an important role in the occurrence and development of knee articular cartilage injury. Furthermore, therapeutically targeting them might be a novel approach for the treatment of keen articular cartilage injury.