A site-resolved two-dimensional quantum simulator with hundreds of trapped ions.

A large qubit capacity and an individual readout capability are two crucial requirements for large-scale quantum computing and simulation1. As one of the leading physical platforms for quantum information processing, the ion trap has achieved a quantum simulation of tens of ions with site-resolved readout in a one-dimensional Paul trap2-4 and of hundreds of ions with global observables in a two-dimensional (2D) Penning trap5,6. However, integrating these two features into a single system is still very challenging. Here we report the stable trapping of 512 ions in a 2D Wigner crystal and the sideband cooling of their transverse motion. We demonstrate the quantum simulation of long-range quantum Ising models with tunable coupling strengths and patterns, with or without frustration, using 300 ions. Enabled by the site resolution in the single-shot measurement, we observe rich spatial correlation patterns in the quasi-adiabatically prepared ground states, which allows us to verify quantum simulation results by comparing the measured two-spin correlations with the calculated collective phonon modes and with classical simulated annealing. We further probe the quench dynamics of the Ising model in a transverse field to demonstrate quantum sampling tasks. Our work paves the way for simulating classically intractable quantum dynamics and for running noisy intermediate-scale quantum algorithms7,8 using 2D ion trap quantum simulators.

[Risk analysis and preventive strategies of implant placement in patients with hypertension].

Recently, among the edentulous patients who undergo dental implants, the proportion of hypertensive patients remains high, which poses a greater challenge for clinicians to operate and to maintain the therapeutic effect. The present review comprehensively summarized clinical researches about the adverse effects on dental implants, outlined molecular mechanisms of the positive effects of various antihypertensive drugs on bone metabolism, and proposed that clinicians should select preventive strategies during preoperative and intraoperative procedures according to the blood pressure of patients with hypertension.

Experimental Realization of Multi-ion Sympathetic Cooling on a Trapped Ion Crystal.

Trapped ions are one of the leading platforms in quantum information science. For quantum computing with large circuit depth and quantum simulation with long evolution time, it is of crucial importance to cool large ion crystals at runtime without affecting the internal states of the computational qubits, thus the necessity of sympathetic cooling. Here, we report multi-ion sympathetic cooling on a long ion chain using a narrow cooling beam focused on two adjacent ions, and optimize the choice of the cooling ions according to the collective oscillation modes of the chain. We show that, by cooling a small fraction of ions, cooling effects close to the global Doppler cooling limit can be achieved. This experiment therefore demonstrates an important enabling step for quantum information processing with large ion crystals.

[NEK2 gene expression in mouse cryptorchidism model and its mechanism involved in apoptosis].

Objective: To observe the expression of NEK2 mRNA and protein in the cryptorchidism mice model, and to explore its role in apoptosis of testicular tissue. Methods: A mouse cryptorchid model was constructed, and the spermatids in the spermatic tubules were observed by HE staining. Apoptosis was detected by Tunel test, and expression of NEK2 mRNA and protein was detected by RT-PCR and immunohistochemistry, respectively. Results: After the mouse cryptorchidism model was successfully constructed, the HE staining results showed that the damage of spermatogonia cells, primary spermatocytes and sperm cells in the seminiferous tubules became more severe with time. The results of Tunel test showed that the number of apoptotic cells first increased and then decreased, 1, 3, 6, 9 and 15 d apoptotic cells were 3.67±2.08 (t=2, P=0.0412), 7.67±1.53 (t=6.325, P=0.003), 17.67±3.51 (t=7.906, P=0.001), 30.67±3.51 (t=14.072, P<0.001) and 14.33±3.21 (t=6.860, P=0.002). The results of immunohistochemistry showed that NEK2 protein was expressed in the nucleus and cytoplasm in normal testis and cryptorchidism. RT-PCR and immunohistochemistry showed that expression of NEK2 mRNA and protein gradually increased after modeling. After reaching the peak, the expression gradually decreased with time, and was significantly lower than the normal control group. Conclusion: The trend of NEK2 expression in cryptorchidism tissue is consistent with the trend of cell apoptosis in cryptorchidism tissue, suggesting that abnormal expression of NEK2 may affect the damage of sperm cells in the seminiferous tubules through apoptosis, leading to infertility in patients with cryptorchidism.

[Correlation analysis between prostate imaging report and data system score and pathological results of prostate cancer].

Objective: To explore the correlation between prostate imaging report and data system (PI-RADS) score and international society of uological pathology (ISUP) grade of prostate cancer (PCa) and the role of PI-RADS score in predicting the pathological features of clinically significant PCa (csPCa), positive surgical margin and pathological upgrade. Methods: The pathologically positive patients with multi-parameter magnetic resonance image (mpMRI) were included in this study. The patients with prostate specific antigen (PSA)<100 µg/L were divided into two groups: biopsy group (n=523) and RP group (n=215). The correlation between PI-RADS score and ISUP grade and the accuracy of predicting csPCa in the two groups were evaluated. In the RP group, the correlation between PI-RADS score and postoperative pathological grade or degradation and positive incisal margin was further discussed. The patients with PSA≥100 µg/L (171cases in biopsy group and 6 cases in RP group) were not included in the statistical analysis, and the results were simply described. Results: The age, prostate volume, and PSA level of biopsy group and RP group was (72±8) years vs (68±7) years, 48.3 (32-57) cm(3) vs 47.2 (32-54) cm(3), and 26.3(10.2-34.2)µg/L vs 21.7 (9.24-23.95)µg/L, respectively. The PI-RADS scores ≤ 3,4, and 5 in the biopsy group were 109,97, and 317 respectively, and those in the RP group were 61,55, and 99 respectively. There were significant differences in the composition of ISUP grades of different PI-RADS scores between the two groups (P<0.001), and there was a positive correlation between the two groups (r=0.493 in the biopsy group, r=0.671 in the RP group, both P<0.001). Using PI-RADS score to predict csPCa, biopsy group (AUC=0.764, P<0.001, 95%CI:0.710-0.819) and RP group (AUC=0.807, P<0.001, 95%CI:0.735-0.879) had certain accuracy. The PI-RADS score combined with PSA could improve the accuracy of csPCa prediction in the biopsy group (AUC=0.795,P<0.001, 95% CI:0.746-0.843) and the RP group (AUC=0.852, P<0.001, 95%CI:0.789-0.915). Compared with the pathological results of biopsy in the RP group, 52.6% of the patients showed upgrade and degrade of ISUP, and there was insignificant difference in the composition of PI-RADS scores between upgraded and degraded patients (P>0.05). However, 41.7%(27/65) of the patients with ISUP grade 1 biopsies had pathological upgrades that the patients with PI-RADS ≤ 3 accounted for 33.3%, while the patients with PI-RADS>3 accounted for 66.7%, and there was significant difference between the two groups (P<0.05). After RP, 43.3% of the patients had positive surgical margins, and the patients with PI-RADS score ≤ 3, 4 and 5 were 13 (14%), 24 (25.8%) and 56 (60.2%), respectively, while the PI-RADS scores of patients with negative surgical margin were 48 (39.3%), 31(25.4%) and 43(35.2%), respectively. There was significant difference between the two groups (P<0.001). The higher the PI-RADS score, the greater the possibility of the positive surgical margin. For the patients with PSA ≥ 100 µg/L, 98.8% (169/171) patients in the biopsy group had a PI-RADS score 5. The pathological results of all patients were csPCa, of which 85.4% (146/171) had ISUP grade ≥ 4. Among them, 6 cases underwent RP, 5 cases had ISUP grade ≥ 4, all surgical margin were positive, 5 cases had seminal vesicle invasion, 3 cases had capsule invasion and 3 cases had positive pelvic lymph nodes. Conclusion: ThePI-RADS score is correlated with the ISUP grade of PCa. Combined with PSA can accurately predict csPCa. At the same time, the higher PI-RADS score, the more likely the patients with positive incisal margin after RP and Gleason score of 3+3=6 at the time of puncture will be upgraded pathologically.

[CD40/TNF receptor associated factor 1 expression and NF-κB-dependent proinflammatory gene expression in rheumatoid arthritis].

Objective: To investigatea cellular/molecular mechanism of the CD40/TRAF1 signalling pathway involved in Rheumatoid arthritis (RA). Methods: 16 patients with active RA and 9 patients with Fractures who underwent total knee or hip replacement in The First Affiliated Hospital of Soochow University were included in the study. Synovial tissues (ST) and serum were obtained from each patient. The CD40, TRAF1, NF-κB p65 were detected by ELISA and Immunohistochemistry in serum and tissue respectively. Real time-PCR (RT-PCR) was applied to measure NF-κB-related gene expression. Results: CD40 and TRAF1 positive area (%) in RA patients were 28.7±5.4, 34.3±4.8 respectively, which were significantly higher (P<0.05) than Fracture controls (21.2±9.5, 21.6±8.7 respectively). The expression of total NF-κB p65, and phospho-NF-κB p65 proteins, as well as NF-κB-related gene expression, including cytokines (TNFα, IL-6), chemokines (MCP-1),and adhesion molecules (ICAM-1) were significantly higher in the ST of RA patients compared to Fracture controls. Conclusion: It is thus possible that the CD40/TRAF1 pathway acted as a positive regulator through NF-κB activation and NF-κB-dependent proinflammatory genes in RA.

[Effect of multimodal analgesia using periprostatic nerve block anesthesia combined with flurbiprofen in transperineal template-guided prostate biopsy].

Objective: To evaluate the effect of multimodal analgesia using periprostatic nerve block anesthesia (PNB) combined with flurbiprofen in patients undergoing transperineal template-guided prostate biopsy (TTPB). Methods: Totally 166 patients (aged (68.2±9.1) years, range: 47 to 81 years) who received TTPB from October 2017 to June 2018 at Department of Urology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University were enrolled prospectively. All the patients were randomly divided into 2 groups. The observation group (n=79) was given flurbiprofen axetil 1 mg/kg intravenously for half an hour before operation and lidocaine was used for PNB before the biopsy. The control group (n=87) was given normal saline combined with PNB. A visual analog scale (VAS) and visual numeric scale (VNS) were used to assess the patients' pain and quantify their satisfaction at two time points: VAS-1 and VNS-1: during biopsy procedure, VAS-2 and VNS-2: 30 min after the procedure. The date were compared by t test, χ(2) test, Fisher exact test and two-way repeated measures anova analysis between the 2 groups. Results: The age, total prostate volume, serum prostate-specific antigen and the number of cores were comparable among the 2 groups (P>0.05). The VAS-1 scores of the control group and the observation group were 2.8±1.7, 1.9±1.2, respectively, and the VNS-1 were 3.1±0.7, 3.4±0.3, respectively. The VAS-1 were significantly lower in observation group than in control group (F=3.904, P=0.000). Conversely, the VNS-1 were higher in observation group (F=3.526, P=0.000). At 30-minute postoperative, the VAS-2 and VNS-2 were 0.7±0.4 and 3.7±0.2 in the control group, respectively. The VAS-2 and VNS-2 were 0.6±0.5 and 3.8±0.1 in the observation group, respectively. There were no significant differences in the pain scores or the satisfaction scores between the 2 groups (F=1.429, 2.825; P=0.136, 0.083). The incidence of overall complications was 26.4% (23/87) in the control group and 25.3% (20/79) in the observation group, with no statistical difference between the 2 groups (χ(2)=0.027, P=0.869). And the complications had no statistically significant difference among the 2 groups including hematuria, urinary retention, infection, hematospermia, vascular and neurological reactions, nausea, vomiting, dizziness, headache, and respiratory depression (P>0.05). Conclusion: The multimodal analgesia induced by PNB and flurbiprofen could effectively relieve the pain for patients who received TTPB.

[Complications of transperineal template-guided prostate mapping biopsy].

Objective: To assess the complications of transperineal template-guided prostate mapping biopsy (TTMB). Methods: Between May 2017 and March 2018, 142 consecutive patients with prior negative transrectal biopsy results and persistently elevated prostate-specific antigen (PSA) were divided into the observation group and the control group randomly. The observation group underwent TTMB and the control group underwent transperineal template-guided prostate saturation biopsy (TTSB). Bleeding, infection, urinary function were recorded after prostate biopsy. Erectile function (ED) was measured at baseline, 1 month, 3 months and 6 months after prostate biopsy using the International Index of Erectile Function (IIEF-5). Results: A mean of 59 cores (from 33 to 116 cores) were obtained in TTMB, and a mean of 23 cores (from 11 to 44 cores) were obtained in TTSB. The positive rate was 50.0% (30/60) in TTMB, and 32.9% (27/82) in TTSB, and there were significant differences between two groups (P<0.05). The incidence of severe hematuria and urinary retention was 8.3% (5/60) and 11.7% (7/60) respectively in TTMB, while 1.2% (1/60) and 11.7% (7/60) respectively in TTSB. There were significant differences between two groups (P<0.05). But there were no significant differences between two groups in the incidence of mild, moderate and total hematuria, hematospermia, perineal hematoma, infection (P>0.05). Rectal bleeding was not observed. In TTMB group, the IIEF-5 scores at baseline, 1 month, 3 months and 6 months were (19.1±4.5), (17.4±4.8), (18.6±4.5), (19.0±4.0), respectively. In TTSB group, the IIEF-5 scores at baseline, 1 month, 3 months and 6 months were (19.7±4.3), (18.2±4.5), (19.1±4.1), (19.6±4.2), respectively. There were significant differences between baseline and 1 month after prostate biopsy in two groups (P<0.05), but there were no significant differences of IIEF-5 score between the two groups (P>0.05). Conclusions: TTMB can improve the positive rate for patients with prior negative transrectal biopsy results and persistently elevated PSA. TTMB has low complication rates, and most side-effects are self-limited. Compared with TTSB, the incidence of urinary retention and severe hematuria increases, but they can be recovered after clinical intervention. ED is transient, and affected for 1 month after the biopsy, but it will be recovered to the baseline after 3 to 6 months. Therefore, TTMB is a safe and reliable procedure.

[The expression and significance of microtubule - driven protein KIF2A in epithelial ovarian cancer].

Objective: To investigate the protein and mRNA expression of KIF2A in ovarian cancer, and to investigate the migration and invasion ability changes in ovarian cancer cell line HO-8910 transfected by KIF2A-siRNA. Methods: Immunohistochemical method was used to detect the expression of KIF2A in 30 cases of ovarian cancer and 20 cases of ovarian normal tissues. The expression of KIF2A mRNA was detected by RT-PCR. The mRNA and protein expression of KIF2A in cell line HO-8910 was detected by RT-PCR and Western blot after transfected by KIF2A-siRNA in vitro. After the transfection, the cell migration and invasion ability were observed by scratch test and transwell experiments. Result: The expression of KIF2A mRNA and protein in HO-8910 was significantly lower than that in normal ovarian tissue (P<0.05). The capacities of migration and invasion of HO-8910 was suppressed notably after the knockdown of KIF2A (P<0.05). Conclusion: KIF2A gene expression was increased in ovarian cancer, and knockdown of KIF2A gene can inhibit the migration and invasion of ovarian cancer cells. It suggested that KIF2A gene may be a new target for the development of ovarian cancer.

[Arthroscopic treatment of eldly with massive rotator cuff tear].

Objective: To investigate the surgical technique and clinical efficacy of arthroscopic treatment of the elderly patients with massive rotator cuff tear. Methods: From June 2012 to June 2015, thirty-six patients with massive rotator cuff tear were treated with arthroscopic and followed up. The visual analog scale(VAS)pain score, University of California Los Angeles (UCLA) scores, Constant scores and American Shoulder and Elbow Surgeons scale(ASES)were used before and after the arthroscopic surgery. Results: All the patients were followed up for average of 18.5 (12 to 30) months.Before arthroscopic surgery, the VAS, UCLA, Constant, ASES were (6.1±2.2), (10.6±4.3), (40.3±10.5) and (28.8±18.5) points; the average flexion of the shoulder was (76.5±42.6)°, the average abduction of the shoulder was (72.4±35.2)°, the average external rotation of the shoulder was(26.6±22.2)° and the average internal rotation of the shoulder was (20.2±6.2)° respectively.These scores were improved to (1.4±1.2), (30.4±5.2), (82.6±12.6), and (78.8±22.6) points, the average flexion of the shoulder was improved to (152.8±25.6)°, the average abduction of the shoulder was improved to (120.6±32.8)°, the average external rotation of the shoulder was improved to (42.6±16.2)° and the average internal rotation of the shoulder was improved to (38.4±5.6)° after one-year follow-up period.Improvement in these scores and range of motion(ROM) were significant difference(P<0.05). Conclusion: Arthroscopic repair can effectively treat the eldly patient with massive rotator cuff tear and obviously improve the function of shoulder joint. The surgery has a clinical application value.

[Primary hypogammaglobulinemia complicated with liver cirrhosis and literature review].

OBJECTIVE: To explore the pathogenesis, treatment and prognosis of primary hypogammaglobulinemia complicated with liver cirrhosis in a child. METHOD: Pathogenesis, treatment and prognosis of X-linked agammaglobulinemia (XLA ) complicated with liver cirrhosis in a child were analyzed in Shanghai Children's Medical Center.Using"primary hypogammaglobulinemia"and"liver cirrhosis"as keywords, literatures were searched from Pubmed and Chinese data of Weipu and Wanfang data from January 1988 to January 2015. RESULT: The patient was a 12 years old boy with the chief complaint of 3 times hematemesis with diagnosis of XLA in the past 7 years. He received treatment with immunoglobulin (Ig) monthly for 6 years. He had no hepatitis C virus( HCV ) infection and serologic tests for autoantibodies were negative. Anti-HBs, anti-HBe and anti-HBc were positive, which revealed previous hepatitis B virus(HBV) infection. Gastroscopy suggested esophageal gastric varices. Liver pathology showed liver cell degeneration, necrosis, fiber tissue hyperplasia and pseudolobuli. After hospitalization the boy underwent liver transplantation (LT). He was given tacrolimus (3 mg/d), prednisone (5 mg/d), lamivudine (150 mg/d) and acyclovir (900 mg/d) by oral administration after LT. After 3 months follow-up, the boy was alive and well with stable results of liver function tests. There were no report in Weipu and Wanfang data. A total of 19 cases, including 12 cases of common variable immunodeficiency, 3 cases of XLA, 2 cases of Hyper-IgM syndrome and 2 cases of congenital hypogammaglobulinemia were obtained from Pubmed published between January 1, 1988 and January 1, 2015. Seventeen of the cases had HCV infection. Two cases had autoimmune hepatitis. Of the HCV infected patients, 15 were given intravenous gamma globulin. Seven of the 19 cases survived. Among 5 cases who received liver transplantation, 3 cases died. CONCLUSION: In addition to HCV infection and autoimmune hepatitis as causes of liver cirrhosis in primary hypogammaglobulinemia, chronic HBV infection is another cause. Intravenous gammaglobulin is an important way of transmitting HCV and HBV infection. The effect of liver transplantation remains to be evaluated via further follow-up and studies.

Characterization and effects of miR-21 expression in esophageal cancer.

The aim of this study was to investigate the expression of miR-21 in esophageal cancer and the impact of miR-21 on apoptosis, invasion, and the expression of target genes in esophageal cancer cells. Fluorescence quantitative polymerase chain reaction analysis was used to detect the expression of miR-21 in human esophageal tissues, adjacent tissues, and an esophageal cancer cell line (TE-13). The antisense miR-21 oligonucleotide was generated commercially using the solid-phase chemical synthesis method. Transient transfection was used to transfect esophageal cancer cells (TE-13 antisense and TE-13 control cells). Flow cytometry and Transwell cell assays were used to detect the apoptosis and invasion of esophageal cancer cells, respectively. The western blot method was used to detect the expression of PTEN, PDCD4, and K-ras proteins. These analyses determined that mir-21 expression significantly increased in esophageal cancer tissues and in TE-13 cells, and that this phenomenon was not associated with staging or lymph node metastasis. The apoptosis rate of TE-13 control cells was lower than that of antisense TE-13 cells indicating an enhanced invasive ability. In tissues adjacent to esophageal cancer and in TE-13 antisense cells, the expression of PTEN and PDCD4 was found to be higher than that in the control group, whereas the expression of K-ras showed the opposite pattern. Together, these results suggest that miR- 21 might be involved in the development and metastasis of esophageal cancer, through interaction with its PDCD4 and K-ras target genes.

Association of miR-21 with esophageal cancer prognosis: a meta-analysis.

The present study aimed to explore the relationship between miRNA expression and survival in patients with esophageal cancer (EC) using meta-analysis. We searched PubMed, EMBASE, CNKI, Wanfang, and ISI Web of Science databases without time restrictions, and extracted relevant data, such as the name of first author, publication year, age, gender, number of case, etc. from the studies included. We calculated the pooled hazard ratios (HRs) using the RevMan 5.2 software. A total of five studies involving 504 subjects were included in the meta-analysis, with the purpose of analyzing the association of miRNA-21 expression with EC prognosis. The pooled HR of elevated versus decreased miR-21 expression in EC was 1.87 [95% confidence interval (CI): 1.37-2.55, P < 0.001], with elevated miR-21 expression being associated with poorer prognosis for patients with EC. Our results support a prognostic role for miR-21 in EC.

Alterations of orexinergic and melanin-concentrating hormone neurons in experimental sleeping sickness.

Human African trypanosomiasis or sleeping sickness is a severe, neglected tropical disease caused by the extracellular parasite Trypanosoma brucei. The disease, which leads to chronic neuroinflammation, is characterized by sleep and wake disturbances, documented also in rodent models. In rats and mice infected with Trypanosoma brucei brucei, we here tested the hypothesis that the disease could target neurons of the lateral hypothalamus (LH) containing orexin (OX)-A or melanin-concentrating hormone (MCH), implicated in sleep/wake regulation. In the cerebrospinal fluid of infected rats, the OX-A level was significantly decreased early after parasite neuroinvasion, and returned to the control level at an advanced disease stage. The number of immunohistochemically characterized OX-A and MCH neurons decreased significantly in infected rats during disease progression and in infected mice at an advanced disease stage. A marked reduction of the complexity of dendritic arborizations of OX-A neurons was documented in infected mice. The evaluation of NeuN-immunoreactive neurons did not reveal significant neuronal loss in the LH of infected mice, thus suggesting a potential selective vulnerability of OX-A and MCH neurons. Immunophenotyping and quantitative analysis showed in infected mice marked activation of microglial cells surrounding OX-A neurons. Day/night oscillation of c-Fos baseline expression was used as marker of OX-A neuron activity in mice. In control animals Fos was expressed in a higher proportion of OX-A neurons in the night (activity) phase than in the day (rest) phase. Interestingly, in infected mice the diurnal spontaneous Fos oscillation was reversed, with a proportion of OX-A/Fos neurons significantly higher at daytime than at nighttime. Altogether the findings reveal a progressive decrease of OX-A and MCH neurons and dysregulation of OX-A neuron diurnal activity in rodent models of sleeping sickness. The data point to the involvement of these peptidergic neurons in the pathogenesis of sleep/wake alterations in the disease and to their vulnerability to inflammatory signaling.

Effects of metallothionein-3 and metallothionein-1E gene transfection on proliferation, cell cycle, and apoptosis of esophageal cancer cells.

Metallothionein (MT)-3 has cell growth inhibitory activity, and is the only currently known MT subtype with unique physiological functions. The expression levels of MT-1E, a subtype of MT-1, were positively correlated with the degree of esophageal cancer malignancy. The present study aimed to investigate the effects of MT-3 and MT-1E gene transfection on the proliferation, cell cycle, and apoptosis of esophageal cancer cells. The cationic liposome method was used to transfect the esophageal cancer strains Eca-109 and TE13. Reverse transcription-polymerase chain reaction was used to detect target gene expression, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction was applied to detect cell proliferation, and flow cytometry was used for cell cycle and apoptosis detection. Esophageal cancer cells with MT-3 and MT-1E gene transfection showed high expression of the foreign target gene and mRNA. Cells with MT-3 gene transfection showed markedly inhibited proliferation (P < 0.05), a significantly higher proportion of cells in the G0/G1 phase (P < 0.05), a significantly lower proportion of cells in the S phase (P < 0.05), and a significantly increased apoptosis rate (P < 0.05). Cells with MT-1E gene transfection did not show significant changes in proliferation, cell cycle, or apoptosis rate (P > 0.05). Therefore, the upregulation of MT-3 gene expression can inhibit esophageal cancer cell proliferation and induce apoptosis, which may be achieved by blocking the tumor cell growth cycle, whereas effects of the MT-1E gene on the proliferation of esophageal cancer cells were not evident.

Protection against titanium particle-induced osteoclastogenesis by cyclooxygenase-2 selective inhibitor.

Wear particle-induced osteoclastogenesis is the most common cause of aseptic loosening in total joint arthroplasty. Although cyclooxygenase (COX)-2, an inducible regulator of prostaglandin E2 (PGE2) synthesis, is known to be involved in osteoclast differentiation, its effect on osteoclastogenesis in response to wear particles remains unclear. In this study, we investigated the role of COX-2 in the regulation of osteoclast differentiation in the osteoclast precursor cell line RAW264.7 stimulated with titanium (Ti) particles. The results showed COX-2 expression in the early stages of RAW264.7 differentiation when stimulated with receptor activator of nuclear factor kappa B ligand (RANKL) and Ti particles. Blockade of COX-2 by celecoxib, a COX-2 selective inhibitor, effectively reduced the expression of PGE2 and inhibited differentiation of RAW264.7 cells into tartrate-resistant acid phosphatase-positive (TRAP+) osteoclastic cells. Quantitative real-time polymerase chain reaction revealed that celecoxib inhibited mRNA expression of RANK, cathepsin K (CPK), TRAP, and the nuclear factor of activated T cells c1 (NFATc1) in RAW264.7 cells stimulated by Ti particles and RANKL. Moreover, exogenous PGE2 reversed the inhibitory effects of celecoxib. These results provide direct evidence that COX-2 dependent PGE2 induced by RANKL and Ti particles is required for osteoclastogenesis and suggests that reduced production of PGE2 by inactivation of COX-2 would provide a promising therapeutic target for the treatment of osteoclastogenesis induced by wear particles.

Thiothymidine combined with UVA as a potential novel therapy for bladder cancer.

BACKGROUND: Thiothymidine (S(4)TdR) can be incorporated into DNA and sensitise cells to DNA damage and cell death following exposure to UVA light. Studies were performed to determine if the combination of S(4)TdR and UVA could be an effective treatment for bladder cancer. METHODS: Uptake and incorporation of S(4)TdR was determined in rat and human bladder tumour cell lines. Measures of DNA crosslinking and apoptosis were also performed. In vivo activity of the combination of S(4)TdR and UVA was investigated in an orthotopic model of bladder cancer in rats. RESULTS: Thiothymidine (200 µM) replaced up to 0.63% of thymidine in rat and tumour bladder cancer cells. The combination of S(4)TdR (10-200 µM) and UVA (1-5 kJ m(-2)) caused apoptosis and cell death at doses that were not toxic alone. Addition of raltitrexed (Astra Zeneca, Alderley Edge, Cheshire, UK) increased the incorporation of S(4)TdR into DNA (up to 20-fold at IC(5)) and further sensitised cells to UVA. Cytotoxic effect was associated with crosslinking of DNA, at least partially to protein. Intravenous administration of S(4)TdR, in combination with UVA delivered directly to the bladder, resulted in an antitumour effect in three of five animals treated. CONCLUSION: These data indicate that the combination of S(4)TdR and UVA has potential as a treatment for bladder cancer, and give some insight into the mechanism of action. Further work is necessary to optimise the delivery of the two components.