Pazopanib stimulates senescence of renal carcinoma cells through targeting nuclear factor E2-related factor 2 (Nrf2).

Renal cell carcinoma (RCC) is the most common kidney cancer with high mortality rate. Pazopanib has been approved for the treatment of RCC. However, the underlying mechanism is not clear. Here, we report a novel finding by showing that treatment with Pazopanib could promote cellular senescence of the human RCC cell line ACHN. Cells were stimulated with 5, 10, and 20 µM Pazopanib, respectively. Cellular senescence was measured using senescence-associated ß-galactosidase (SA-ß-Gal) staining. Western blot analysis and real-time polymerase chain reaction were used to measure the mRNA and protein expression of nuclear factor E2-related factor 2 (Nrf2), γH2AX, human telomerase reverse transcriptase (hTERT), telomeric repeat binding factor 2 (TERF2), p53 and plasminogen activator inhibitor (PAI). First, we found that exposure to Pazopanib reduced the cell viability of ACHN cells. Additionally, Pazopanib induced oxidative stress  by increasing the production of reactive oxygen species, reducing the levels of glutathione peroxidase, and promoting nuclear translocation of Nrf2. Interestingly, Pazopanib exposure resulted in DNA damage by increasing the expression of γH2AX. Importantly, Pazopanib increased cellular senescence and reduced telomerase activity. Pazopanib also reduced the gene expression of hTERT but increased the gene expression of TERF2. Correspondingly, we found that Pazopanib increased the expression of p53 and PAI at both the mRNA and protein levels. To elucidate the underlying mechanism, the expression of Nrf2 was knocked down by transduction with Ad- Nrf2 shRNA. Results indicate that silencing of Nrf2 in ACHN cells abolished the effects of Pazopanib in stimulating cellular senescence and reducing telomerase activity. Consistently, knockdown of Nrf2 restored the expression of p53 and PAI in ACHN cells. Based on these results, we explored a novel mechanism whereby which Pazopanib displays a cytotoxicity effect in RCC cells through promoting cellular senescence mediated by Nrf2.

Non-destructive testing of interfacial stiffness based on spring model for diffusion bonding interface of titanium alloy components with complex surface.

Ultrasonic testing is an important non-destructive testing method, which is sensitive to the defects in the diffusion bonding interface. Ultrasonic testing of diffusion bonding interfaces in complex-surface components is a challenge due to the geometry and the weak echo signal of the diffusion bonding defects. This paper proposes an interfacial stiffness characterization method based on the spring model for the ultrasonic testing of the diffusion bonding interface of titanium alloy complex-surface component. Finite element models for ultrasonic field are established to analyze the diffusion bonding defects response, the effect of complex surface, and the inconsistency of the bonding interface depth in ultrasonic testing of the titanium alloy complex-surface component. 15 MHz is recommended as the testing frequency of the diffusion bonding interface. Ultrasonic C-scan experiments are conducted using specimens with embedded artificial defects and a titanium alloy complex-surface component. The simulation and experimental results show that the novel interfacial stiffness characterization method can be applied to ultrasonic testing of the diffusion bonding interface (inclination angle less than 14°) in complex-surface components, and the ability to test defects at the diffusion bonding interface can be improved.

Initial experience with surrounding en bloc transurethral resection of bladder tumor and simultaneous intravesical treating for non-muscle invasive bladder cancer.

PURPOSE: The high recurrence rate after traditional transurethral resection of bladder tumor (TURBT) remains a challenge for management of non-muscle invasive bladder tumor (NMIBC). The aim of this study was to evaluate feasibility, efficacy and safety of surrounding en bloc resection using a general wire bipolar loop electrode and simultaneous intravesical chemotherapy. METHODS: We retrospectively analyzed data of 111 consecutive patients with NMIBC treated from June 2018 to December 2021. These patients underwent conventional TURBT and immediate intravesical chemotherapy (n = 45) or surrounding en bloc TURBT and simultaneous intravesical chemotherapy in the Urology Department of Harbin Medical University Cancer Hospital, The former and latter were defined as the conventional TURBT group and the surrounding en bloc TURBT group, respectively. All patients were followed up from 6 to 40 months, with an average of 24 months. Demographic characteristics, location and number of tumors, perioperative and postoperative data, pathological results and recurrence were documented. RESULTS: There were no significant differences in clinicopathological data between the conventional TURBT group (n = 45) and the surrounding en bloc TURBT group (n = 66). Operative time and complications associated with TURBT were comparable in the two groups. Recurrent tumors were found during follow-up in 2 (3.0%) of 66 patients in the surrounding en bloc group and 9 (20%) of 45 patients in the conventional group (p < 0.05). Lower urinary tract symptoms developed in 2 (3.0%) of 66 patients after surrounding en bloc TURBT and in 11(24.4%) of 45 patients after conventional TURBT (p < 0.05). CONCLUSION: Surrounding en bloc TURBT and simultaneous intravesical chemotherapy might significantly decrease the recurrence rate of NMIBC, and showed favorable safety and tolerability profiles. The general bipolar loop electrode was appropriate to complete the procedure.

A novel non-destructive testing method for turbine disks using dual array ultrasonic transducer.

A novel dual array inspection method for detecting the diffusion bonding defects of superalloy turbine disk has been proposed in this study. The influence of relative position between the planar defect and acoustic source has been analysed, and based on which, the transmission and reception algorithm for the dual array method has been proposed. The time delay law of the dual array transducer for the complex turbine disk structure has been investigated. Finite-difference time-domain theory has been used to establish the numerical model of the dual array method. In the numerical simulations, the novel method has been applied for the superalloy turbine disk specimen with prefabricated defects at the depth of 18.3 m and 28.3 mm. Furthermore, the corresponding experiment has been conducted and verifies the reliability of the simulation. The novel method shows advantages in detecting small diffusion bonding defects in complex structure, assisting the manufacture of superalloy turbine disks, and ensuring the safety of aircrafts.

Baseline Disease Activity Predicts Achievement of cDAPSA Treatment Targets With Apremilast: Phase III Results in DMARD-naïve Patients With Psoriatic Arthritis.

OBJECTIVE: The probability of achieving Clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) treatment targets (remission [REM], low disease activity [LDA]) was evaluated following apremilast monotherapy in disease-modifying antirheumatic drug (DMARD)-naïve patients with psoriatic arthritis (PsA) based on baseline disease activity. METHODS: This post hoc probability analysis of PALACE 4, a phase III, multicenter, randomized, placebo-controlled study, evaluated shifting across cDAPSA categories from baseline to week 52 and included DMARD-naïve patients receiving apremilast 30 mg BID with available baseline cDAPSA data. Changes in articular/extraarticular manifestations were evaluated in patients with week 52 cDAPSA components. cDAPSA treatment target achievement was assessed in a subgroup with baseline extraarticular PsA manifestations (skin involvement, enthesitis, dactylitis). RESULTS: Of 175 apremilast-treated patients in the probability analysis, 66.3% were in high disease activity (HDA) and 31.4% in moderate disease activity (ModDA) at baseline. Approximately twice as many patients in ModDA at baseline reached REM/LDA at week 52 vs those in HDA (61.7% vs 28.2%). Achieving cDAPSA treatment targets was associated with reductions in articular (swollen/tender joints) and extraarticular (skin involvement, enthesitis, dactylitis, functional disability) disease activity. Similar treatment target achievement rates were observed in the subgroup with ≥ 1 extraarticular PsA manifestation (n = 126; ModDA: 66.7%, HDA: 32.2%). CONCLUSION: Apremilast-treated patients with baseline ModDA had higher probability of achieving cDAPSA treatment targets than patients with HDA. Resolution and/or near resolution of articular and/or extraarticular PsA manifestations was achieved by patients in REM/LDA at week 52. Consistent treatment target achievement was observed in patients with 1 or multiple extraarticular manifestations of active PsA.

A Method for Prediction of Ultrasonic Detectability of Interface Gap Defects on TC4 Diffusion-Bonded Joints.

An analysis method for the detectability of defects on the TC4 (Ti-6Al-4V) diffusion bonding interface was proposed in this study. First, a semi-analytical model of the liquid-solid coupling acoustic field with attenuation characteristics was constructed. Based on this, a method for the selection of transducer parameters was investigated for effective focus on the diffusion bonding interface. Second, according to the characteristics of defects on the diffusion bonding interface, an acoustic response model for diffusion bonding defects was established based on Kirchhoff approximation. The detectability of defects on the diffusion bonding interface was analyzed using transducers of different frequencies with different diffusion bonding interface gaps. Finally, an experiment was conducted to verify the reliability of the simulation. The analysis method proposed shows the advantages in the selection of suitable parameters for detecting specific diffusion bonding interface gaps, providing theoretical predictions of the detectability of diffusion bonding interface defects.

Apremilast monotherapy for long-term treatment of active psoriatic arthritis in DMARD-naïve patients.

OBJECTIVES: Apremilast monotherapy was evaluated up to 5 years in PALACE 4 (fourth PsA Long-term Assessment of Clinical Efficacy study) DMARD-naïve patients with PsA. METHODS: Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg or apremilast 20 mg twice a day. Placebo patients were rerandomized to apremilast at week 16 or 24. Double-blind apremilast continued to week 52, with a 4-year open-label extension (≤260 weeks of exposure). Analyses through week 260 were based on observed data. RESULTS: A total of 527 patients were treated. Among patients randomized to apremilast 30 mg at baseline, 45.5% completed week 260. At study end, 24.8% reported conventional synthetic DMARD or steroid use for any reason. At week 260, 65.8%/39.0%/20.3% of apremilast 30 mg patients achieved ACR20/ACR50/ACR70 responses, respectively. PsA sign and symptom improvements were sustained up to week 260 with continued treatment, including reductions in swollen (84.8%) and tender (76.4%) joint counts. Among apremilast 30 mg patients with baseline enthesitis or dactylitis, 71.2% achieved a Maastricht Ankylosing Spondylitis Enthesitis Score of 0 and 95.1% achieved a dactylitis count of 0. Over 50% of patients achieved a HAQ Disability Index minimal clinically important difference (≥0.35). In patients with ≥3% baseline psoriasis-involved body surface area, 60.3% and 47.6% achieved ≥50% and ≥75% improvement in Psoriasis Area and Severity Index scores, respectively. Patients continuing apremilast 20 mg also demonstrated consistent, sustained improvements. The most common adverse events were diarrhoea, nausea, headache, upper respiratory tract infection and nasopharyngitis. No new safety concerns were observed long term. CONCLUSIONS: Apremilast led to sustained PsA efficacy up to 260 weeks and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov (http://clinicaltrials.gov), NCT01307423.

Articular and Extra-Articular Benefits in ACR20 Non-responders at Week 104 Treated With Apremilast: Pooled Analysis of Three Randomized Controlled Trials.

INTRODUCTION: PALACE 1, 2, and 3 were phase 3 studies aimed to evaluate apremilast efficacy and safety in patients with active psoriatic arthritis (PsA) despite prior treatment with conventional disease-modifying anti-rheumatic drugs and/or biologics. The pooled analysis reported here further characterized the clinical outcomes associated with long-term apremilast exposure in patients failing to achieve ≥ 20% improvement in the American College of Rheumatology response criteria (ACR20) at Week 104. METHODS: Patients randomized to apremilast 30 mg twice daily at baseline and classified as ACR20 non-responders (ACR20NRs) or ACR20 responders (ACR20Rs) at Week 104 were included. Efficacy outcomes included change from baseline to Week 104 in ACR core components and other endpoints. RESULTS: At Week 104, a total of 109 patients were ACR20NRs and 193 were ACR20Rs. As expected, the ACR20R group had improvements in all indices assessed. The ACR20NR group demonstrated substantial mean improvements from baseline in swollen joint count (SJC; - 58%), tender joint count (TJC; - 42%), and Physician's Global Assessment of Disease Activity (PhGA; - 44%); resolution of enthesitis (34%) and dactylitis (68%); and achievement of ≥ 75% reduction from baseline Psoriasis Area and Severity Index scores (among patients with psoriasis involving ≥ 3% of the body surface area) (36%). CONCLUSION: Despite not fulfilling a formal ACR20 response at Week 104, ACR20NRs experienced sustained improvements in several PsA core domains, including SJC, TJC, enthesitis, dactylitis, and psoriasis, as well as the PhGA (visual analog scale) scores, with apremilast treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01172938, NCT01212757, and NCT01212770.

The Role of the Hematopoietic Cell-Specific Protein 1-Associated Protein X-1 in Human Papillomavirus 16 E2-Induced Human Cervical Squamous Carcinoma Cell Apoptosis via a Mitochondria-Dependent Pathway.

OBJECTIVES: Human papillomavirus 16 (HPV 16) E2 is a transcriptional regulator that plays a key role in regulating a variety of biological responses. Hematopoietic cell-specific protein 1-related protein X-1 (HAX-1) is a mitochondrial membrane protein, and the HAX-1 gene is involved in the occurrence, growth, invasion, and metastasis of various human malignant tumors. The purpose of this study was to investigate the relationships among HPV 16 E2, the role of HAX-1 gene, and the underlying intracellular apoptotic mechanism of human cervical squamous carcinoma cells (C33a and SiHa). METHODS: In this study, HAX-1 expression was examined using real-time polymerase chain reaction, Western blot, and immunohistochemical staining analysis. Apoptosis of cells was assessed by flow cytometry. The mitochondrial function was assessed by the mitochondrial copy number, reactive oxygen species (ROS) generation, the mitochondrial membrane potential (ΔΨm), and mitochondrial morphology. RESULTS: Our study demonstrated that the expression of the HAX-1 gene was significantly increased in human cervical carcinoma tissues relative to noncancerous cervix tissues. HPV 16 E2 inhibited HAX-1 protein expression. Overexpression of HAX-1 increased the mitochondrial copy number, decreased the production of ROS, and maintained the integrity of the mitochondrial membrane and morphology. So, enhanced expression of the HAX-1 gene could abrogate the HPV 16 E2-induced cell apoptosis. CONCLUSION: Therefore, these data support a mechanism that HAX-1 plays a crucial role in HPV 16 E2-induced human cervical squamous carcinoma cell apoptosis in a mitochondrial-dependent manner.

Can Circulating Cell-Free DNA or Circulating Tumor DNA Be a Promising Marker in Ovarian Cancer?

In recent years, the studies on ovarian cancer have made great progress, but the morbidity and mortality of patients with ovarian cancer are still very high. Due to the lack of effective early screening and detecting tools, 70% of ovarian cancer patients are diagnosed at an advanced stage. The overall survival rate of ovarian cancer patients treated with surgical combined with chemotherapy has not been significantly improved, and they usually relapse or resist chemotherapy. Therefore, a novel tumor marker is beneficial for the diagnosis and prognosis of patients with ovarian cancer. As the index of "liquid biopsy," circulating cell-free DNA/circulating tumor DNA (cfDNA/ctDNA) has attracted a lot of attention. It has more remarkable advantages than traditional methods and gives a wide range of clinical applications in kinds of solid tumors. This review attempts to illuminate the important value of cfDNA/ctDNA in ovarian cancer, including diagnosis, monitoring, and prognosis. Meanwhile, we will present future directions and challenges for detection of cfDNA/ctDNA.

LncRNA HOTAIR induces sunitinib resistance in renal cancer by acting as a competing endogenous RNA to regulate autophagy of renal cells.

BACKGROUND: Cell autophagy has been proposed to be involved in drug resistance therapy. However, how the long non-coding RNA (lncRNA) reduces risks of drug resistance in renal cancer (RC) cells needs a thorough inquiry. This study was assigned to probe the effect and mechanism of HOTAIR on sunitinib resistance of RC. METHODS: Clinical RC tissues and para-carcinoma tissues were obtained to detect the expressions of miR-17-5p, HOTAIR and Beclin1. Sunitinib-resistant cells (786-O-R and ACHN-R) were constructed using parental RC cells (786-O and ACHN). The resistance of 786-O-R and ACHN-R cells to sunitinib was examined. Western blot and qRT-PCR were assayed to obtain the expressions of miR-17-5p, HOTAIR and Beclin1. The effects of HOTAIR knockdown or miR-17-5p overexpression/knockdown on cell autophagy and sunitinib resistance were measured by MDC staining, immunofluorescence and Western blot. The sensitivity of RC cells to sunitinib and change in cell clone formation after sunitinib treatment were assessed by CCK-8 assay and colony formation assay, respectively. The relationships among HOTAIR, miR-17-5p and Beclin1 were verified by dual-luciferase reporter gene and RIP assay. The role of HOTAIR knockdown in sunitinib resistance was verified in nude mice. RESULTS: HOTAIR expression in sunitinib-resistant cells is higher than that in parental cells. Knockdown of HOTAIR in sunitinib-resistant cells lead to refrained sunitinib resistance and cell autophagy both in vivo and in vitro. Activation of autophagy could raise resistance to sunitinib in RC cells, while inhibition of autophagy could improve the sensitivity of sunitinib-resistant cells to sunitinib. HOTAIR could compete with miR-17-5p to regulate Beclin1 expression. Knockdown of miR-17-5p in parental cells increases cell resistant to sunitinib, and overexpression of miR-17-5p in sunitinib-resistant cells increases cell sensitive to sunitinib. CONCLUSION: HOTAIR negatively targets miR-17-5p to activate Beclin1-mediated cell autophagy, thereby enhancing sunitinib resistance in RC cells.

Long-Term Safety and Tolerability of Apremilast Versus Placebo in Psoriatic Arthritis: A Pooled Safety Analysis of Three Phase III, Randomized, Controlled Trials.

OBJECTIVE: Psoriatic arthritis (PsA) requires long-term treatment, yet safety concerns and monitoring requirements make maintenance a challenge. This analysis of pooled Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) 1, 2, and 3 data describes 3-year apremilast safety and tolerability in PsA. METHODS: Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg twice daily, or apremilast 20 mg twice daily. Placebo patients were re-randomized to apremilast 30 mg twice daily or 20 mg twice daily at week 16 (early escape) or 24. Double-blind treatment continued to week 52; patients could continue apremilast during an open-label, long-term treatment phase. RESULTS: In total, 1493 patients received at least one dose of study medication and were included in the safety population (placebo: n = 495; apremilast 30 mg: n = 497; apremilast 20 mg: n = 501). Among patients receiving apremilast, 53.2% (767/1441) completed 3 years of treatment. Greater rates of adverse events (AEs) were reported with apremilast (61.1%; exposure-adjusted incidence rate [EAIR]/100 patient-years, 265.1) versus placebo (47.5%; EAIR/100 patient-years, 200.7) in the placebo-controlled period. During weeks 0 to ≤52, the most common AEs occurring in apremilast-exposed patients were diarrhea (13.9%; EAIR/100 patient-years, 18.6), nausea (12.3%; EAIR/100 patient-years, 16.0), headache (9.4%; EAIR/100 patient-years, 12.1), upper respiratory tract infection (9.1%; EAIR/100 patient-years, 11.5), and nasopharyngitis (6.2%; EAIR/100 patient-years, 7.7). Most AEs were mild/moderate with apremilast exposure ≤156 weeks. Rates of depression remained low (EAIR/100 patient-years, 1.8). Major adverse cardiac events (EAIR/100 patient-years, 0.5), malignancies (EAIR/100 patient-years, 0.9), and serious opportunistic infections (EAIR/100 patient-years, 0.0) were infrequent over the 3-year exposure period. Discontinuation rates due to AEs were low (<7.5%) across all apremilast-exposure periods. Incidences of clinically meaningful abnormalities in postbaseline laboratory values was low; most values returned to baseline levels with continued treatment and without intervention. CONCLUSION: Apremilast demonstrated a favorable safety profile and was well tolerated up to 156 weeks.

Total pelvic exenteration and a new model of diversion for giant primitive neuroectodermal tumor of prostate: A case report and review of the literature.

The present study reports a rare primitive neuroectodermal tumor (PNET) of prostate. A 27-year-old male was admitted to Harbin Medical University Cancer Hospital (Harbin, China) for dysuria and dyschezia. Magnetic resonance imaging (MRI) revealed a large mass that may involve the bladder and rectum next to the prostate. Histopathological analysis of biopsy of prostate indicated mesenchymal origin tumor, and immunohistochemistric staining confirmed diagnosis of PNET of prostate. En bloc total pelvic exenteration and double barrel sigmoidostomy were performed. Double stomas in the skin incision were used for fecal and urinary diversion, respectively. Short-term outcome is satisfactory, while long-term efficacy remains to be poor. Clinical features of PNET of prostate should be paid much more attention and radical surgery and adjuvant chemotherapy should be recommended.

Treatment-to-Target With Apremilast in Psoriatic Arthritis: The Probability of Achieving Targets and Comprehensive Control of Disease Manifestations.

OBJECTIVE: The present study was undertaken to evaluate the probability of achieving the Clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) treatment targets of remission or low disease activity (LDA) with apremilast based on disease activity categories and corresponding responses in arthritis and other domains of psoriatic arthritis (PsA) not included in the cDAPSA. METHODS: Pooled analyses from the Psoriatic Arthritis Long-term Assessment of Clinical Efficacy studies 1, 2, and 3 were performed. Probability analyses assessing the likelihood of achieving cDAPSA treatment targets by week 52 were performed using multiple imputation for discontinuations and missing values. Longitudinal analyses were performed in patients grouped by cDAPSA category at week 52. RESULTS: Among 494 patients in the probability analyses, 46.9% with moderate disease activity and 24.9% with high disease activity at baseline achieved treatment targets (remission or LDA) by week 52. For patients with moderate disease activity at baseline, small improvements (cDAPSA reductions ≥30%) by week 16 were associated with achieving targets. Patients achieving remission or LDA by week 16 had high probabilities of remaining at treatment targets at week 52. Of 375 patients with cDAPSA components available at week 52, achieving targets with apremilast was associated with continuous disease activity improvements and no or mild arthritis and other PsA manifestations. CONCLUSION: The probability of achieving treatment targets (remission or LDA) at week 52 was greater for patients with moderate versus high disease activity at baseline. At a mean level, partial improvements by week 16 were associated with achieving treatment targets. Patients receiving apremilast who achieved cDAPSA targets by week 52 also had no or mild arthritis or other PsA manifestations.

The vitamin D receptor (VDR) protects pancreatic beta cells against Forkhead box class O1 (FOXO1)-induced mitochondrial dysfunction and cell apoptosis.

Vitamin D deficiency is identified as a risk factor for gestational diabetes mellitus (GDM). Forkhead box class O1 (FoxO1) is closely related to GDM; however, the role of vitamin D deficiency and the underlying pathogenesis of GDM has not been elucidated. Serum vitamin D level was detected using chemiluminescence immunoassay. FOXO1 expression was examined using Real-time polymerase chain reaction (PCR), western blot and immunocytochemistry analysis. Apoptosis of cells was assessed by flow cytometry. Mitochondrial function was assessed via reactive oxygen species (ROS) generation and changes in the mitochondrial membrane potential (ΔΨm). Our study demonstrated that vitamin D levels were significantly lower in 40 GDM patients. The silencing of the vitamin D receptor (VDR) decreased cell survival and increased both FoxO1 mRNA and protein expression. Overexpression of FoxO1 could cause the mitochondrial dysfunction (including production of ROS and decrease of mitochondrial membrane potential (ΔΨm)) and cell apoptosis. However, Overexpression of VDR and vitamin D treatment could induce the cell survival and alleviate the FoxO1-induced cell apoptosis, furthermore, vitamin D treatment or silencing of FoxO1 gene could reverse the ROS-induced cell apoptosis. Therefore, our results support that vitamin D may protect FoxO1-induced pancreatic beta cell apoptosis, which suggests that vitamin D may have beneficial effects in preventing and treating GDM.

Long-term experience with apremilast in patients with psoriatic arthritis: 5-year results from a PALACE 1-3 pooled analysis.

BACKGROUND: The efficacy and safety of apremilast were assessed in patients with psoriatic arthritis (PsA) in three phase III clinical trials with similar designs (PALACE 1, 2, and 3). METHODS: Following a 24-week, randomized (1:1:1 to apremilast 30 mg twice daily, 20 mg twice daily, or placebo), double-blind phase and a 28-week blinded active treatment phase, patients could receive apremilast in open-label extension studies for an additional 4 years. Eligible adult patients had active PsA for ≥ 6 months and three or more swollen joints and three or more tender joints despite prior treatment with disease-modifying anti-rheumatic drugs. RESULTS: A total of 1493 randomized patients received one or more doses of study medication (placebo: n = 496; apremilast 30 mg twice daily: n = 497; apremilast 20 mg twice daily: n = 500). In patients continuing apremilast treatment, response was sustained without new safety issues. At week 260, 67.2% of remaining patients achieved an ACR20 response, and 44.4% and 27.4% achieved ACR50 and ACR70 responses, respectively. Among patients with baseline enthesitis and dactylitis, 62.4% achieved a Maastricht Ankylosing Spondylitis Enthesitis Score of 0 and 80.9% achieved a dactylitis count of 0, respectively. In patients who had ≥ 3% baseline psoriasis body surface area involvement, 43.6% achieved ≥ 75% reduction from the baseline Psoriasis Area and Severity Index scores. The most commonly reported adverse events (AEs) were diarrhea, nausea, headache, upper respiratory tract infection, and nasopharyngitis, with most diarrhea and nausea AEs occurring within the first 2 weeks of treatment and usually resolving within 4 weeks. Reported rates of depression during the study were low (≤ 1.8%). The majority of patients maintained their weight within 5% of baseline during the study. No new safety concerns or increases in the incidence or severity of AEs were observed over the long term. CONCLUSIONS: Apremilast maintained clinical benefit and a favorable safety profile for up to 5 years among patients with PsA. TRIAL REGISTRATION: ClinicalTrials.gov NCT01172938 , NCT01212757 , NCT01212770.

The role of eukaryotic translation initiation factor 5A-1 (eIF5A-1) gene in HPV 16 E6 induces cell growth in human cervical squamous carcinoma cells.

Human Papillomavirus (HPV) is considered as the major risk factor for the development and progression of cervical cancer. The high expression of HPV 16 E6 may be the causative factor for induction and maintenance of the transformed phenotype. These oncoproteins would interact with several intracellular proteins, such as eukaryotic translation initiation factor 5A-1 (eIF5A-1) that is essential for proliferation of eukaryotic cells. Our study explored the expression level of HPV 16 E6 and eIF5A-1 in human cervical squamous carcinoma samples and the adjacent non-cancerous cervix samples. Both C33a cells and SiHa cells transfected with a vector encoding HPV 16 E6 resulted in increase of eIF5A-1 expression level and enhancement of viability, migration and proliferation of these cells, furthermore, these effects in both C33a cells and SiHa cells could be abrogated by treatment with eIF5A-1 small-interfering RNA (siRNA) or the specific inhibitors ciclopirox (CPX) that was used to inhibit the function of eIF5A-1 via blocking the main enzymes deoxyhypusine hydroxylase (DOHH). Our results support that the silencing the eIF5A-1 gene or blocking the DOHH could induce the apoptosis of HPV 16 E6-infected cervical carcinoma cells. Thus might provide a new approach to preventing and treating cervical cancer.

Caspase-10, matrix metalloproteinase-9 and total laminin are correlated with the tumor malignancy of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a common malignant kidney tumor, the pathogenesis of which remains unclear. The aim of the present study was to investigate whether caspase-10, matrix metalloproteinase-9 (MMP-9) and total laminin (LM) were involved into the pathogenesis of ccRCC. The levels of caspase-10, MMP-9 and total LM were analyzed by ELISA in tumor tissues and adjacent non-malignant tissues of 27 patients with ccRCC. The results revealed that caspase-10 levels in the tumor tissues were significantly higher than those in the adjacent non-malignant tissues (P<0.05). The MMP-9 levels in the tumor tissues were significantly lower than those in adjacent non-malignant tissues (P<0.01). The total LM levels in tumor tissues revealed no statistical difference with those in the adjacent non-malignant tissues (P=0.757). Additionally, caspase-10 levels were positively correlated with MMP-9 levels (P<0.001), but negatively correlated with total LM levels (P<0.05) in tumor tissues. Correlation analyses with clinical data of patients with ccRCC, revealed that caspase-10 levels (P<0.05) and MMP-9 levels (P<0.001) in tumor tissues were positively correlated with tumor grades of ccRCC, whereas total LM levels were positively correlated with tumor size (P<0.05). The results of the present study suggested that interactions between caspase-10, MMP-9 and LM are likely involved in the pathogenesis of ccRCC. A deeper understanding of the correlation between caspase-10, MMP-9 and LM would aid the clarification of pathogenesis of ccRCC.

Therapeutic benefit of apremilast on enthesitis and dactylitis in patients with psoriatic arthritis: a pooled analysis of the PALACE 1-3 studies.

OBJECTIVE: The Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial programme findings demonstrated that apremilast, an oral phosphodiesterase 4 inhibitor, is effective for treating psoriatic arthritis (PsA). Enthesitis and dactylitis are difficult-to-treat features of PsA leading to disability and affecting quality of life. PALACE 1, 2 and 3 data were pooled to assess the efficacy of apremilast on enthesitis and dactylitis outcomes in patients with these conditions at baseline. METHODS: Patients with enthesitis (n=945) or dactylitis (n=633) at baseline were analysed after receiving double-blind treatment with placebo, apremilast 30 mg two times per day or apremilast 20 mg two times per day up to 52 weeks and continuing up to 5 years. Data were analysed through 156 weeks. Enthesitis was evaluated by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and dactylitis via dactylitis count. RESULTS: At week 24, patients receiving apremilast 30 mg two times per day demonstrated a significantly greater mean change in enthesitis (-1.3 vs -0.9; p<0.05) and dactylitis (-1.8 vs -1.3; p<0.01) vs placebo. Patients in the 30 mg dose group showed significantly greater mean (-23.6% vs -7.0%; p<0.05) and median (-50.0% vs -21.1%; p<0.05) per cent changes in MASES; mean and median per cent changes in dactylitis count were numerically, but not significantly, different for either apremilast dose in patients with dactylitis. In the patient population remaining on apremilast, observed mean and median improvements in both conditions were sustained through 156 weeks. CONCLUSION: Apremilast is effective for the treatment of active PsA, including improvements in enthesitis and dactylitis up to 3 years. TRIAL REGISTRATION NUMBERS: NCT01172938, NCT01212757 and NCT01212770.

Overexpression of ATP citrate lyase in renal cell carcinoma tissues and its effect on the human renal carcinoma cells in vitro.

ATP citrate lyase (ACLY) is a key enzyme of lipogenesis in cells. However, ACLY expression in renal cell carcinoma (RCC) and its association with clinicopathological parameters remain unclear. The present study aimed to evaluate ACLY expression levels in RCC and adjacent normal tissues. This study included 33 patients with clear cell RCC (ccRCC). ACLY protein was assayed using immunohistochemistry and western blotting methods. ACLY mRNA expression was determined by reverse transcription-quantitative polymerase chain reaction. Serum ACLY concentrations were measured using the ELISA. Compared with adjacent normal tissues, significantly higher levels of ACLY protein expression were observed in all of the ccRCC tissues (P<0.05). ACLY protein levels were positively associated with the T stage and nuclear grade of RCC. ACLY immunostaining was located in the cytoplasm and nucleus. ACLY protein levels and ACC1 mRNA expression in RCC tissues were significantly higher compared with that in adjacent normal tissues (P<0.05). There were no significant differences in serum ACLY concentrations between patients with RCC and health controls (P>0.05). Preliminary evaluation of ACLY function showed that ACLY small interfering RNA downregulation inhibited RCC cell proliferation and migration, but promoted RCC cell apoptosis. ACLY may be a novel biomarker for the evaluation of biological aggressiveness and may be a potential target for RCC treatment.