Fabrication of pH-degradable supramacromolecular microgels with tunable size and shape via droplet-based microfluidics.

This study presents a versatile method to synthesize stimuli-responsive microgels with supramolecular cross-links exhibiting tunable size and shape via droplet-based microfluidics. The natural polyphenol tannic acid (TA) is used to cross-link poly(N-vinylcaprolactam) (PVCL) chains in aqueous droplets by the formation of hydrogen bonds and hydrophobic interactions between the phenolic groups of TA and the carbonyl group and the hydrophobic segments of lactam ring of PVCL chains. The obtained microgels exhibit diameters in the range of 130-150µm in swollen state in aqueous solution. Synthesized microgels exhibit pH-responsive behavior: at low pH microgels deswell and shrink due to the protonation of phenolic groups and enhanced hydrophobic interactions; at high pH microgels swell and disintegrate due to the deprotonation of phenolic groups and destruction of hydrogen bonds with PVCL chains. Additionally, we present supramacromolecular microgels in cylindrical shape with different aspect ratios using a new design of microfluidic chip by varying flow rates at high concentration of the prepolymerized precursor combined with rapid pH-triggered on-chip gelation. Furthermore, developed synthesis methodology allows on-chip encapsulation of colloidal objects into large supramacromolecular microgels during the cross-linking step. The complete and fast release of objects by pH-triggered degradation indicates that the pH-responsive supramacromolecular microgels can be used for controlled loading/release of various payloads, like probiotics. Moreover, cell studies of L929 fibroblast clearly show the biocompatibility of the microgels.

Adjuvant durvalumab for esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy: a placebo-controlled, randomized, double-blind, phase II study.

BACKGROUND: We evaluated the efficacy of adjuvant durvalumab after neoadjuvant concurrent chemoradiotherapy (CCRT) in patients with esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: This randomized, double-blind, phase II study included patients with ESCC who underwent curative surgery after neoadjuvant CCRT. Patients were randomized to receive either durvalumab (20 mg/kg/i.v. every 4 weeks for 12 months) or placebo in a 1:1 ratio and were stratified by age and pathologic tumor stage. The primary endpoint was disease-free survival (DFS). RESULTS: Between March 2016 and June 2018, 86 patients were randomized to the durvalumab (n = 45) or placebo (n = 41) arm. The median follow-up duration was 38.7 months. There was no difference in DFS [hazard ratio (HR) 1.18, 95% confidence interval (CI) 0.62-2.27, P = 0.61] or overall survival (HR 1.08, 95% CI 0.52-2.24, P = 0.85) between the two arms. Subgroup analysis was performed for patients for whom the post-CCRT programmed death-ligand 1 (PD-L1) expression profile could be assessed (n = 54). In the PD-L1-positive group, based on tumor proportion score ≥1%, durvalumab was associated with longer overall survival compared with the placebo (36-month survival rate: 94% versus 64%; HR 0.42, 95% CI 0.10-1.76), while in the PD-L1-negative group, it was associated with shorter overall survival (42% versus 55%; HR 1.53, 95% CI 0.48-4.83), showing the tendency of interaction between post-CCRT PD-L1 status and adjuvant durvalumab therapy for overall survival (interaction P = 0.18). CONCLUSIONS: We failed to demonstrate that adjuvant durvalumab improved survival after neoadjuvant CCRT in patients with ESCC. However, post-CCRT PD-L1 expression could predict the survival of patients who receive adjuvant durvalumab after neoadjuvant CCRT, which needs to be validated.

Relationship Between Sexual Function and Pelvic Floor and Hip Muscle Strength in Women With Stress Urinary Incontinence.

INTRODUCTION: The pelvic floor muscle (PFM) could affect female sexual functions. The hip muscles are morphologically and functionally linked to PFM and are important elements of female sexual attraction. AIM: To determine the relationship between female sexual function and hip muscle strength and PFM functions in women with stress urinary incontinence (SUI). METHODS: A total of 42 women with SUI were recruited in this study. Female sexual function was measured using the pelvic organ prolapse urinary incontinence sexual function questionnaire (PISQ). PFM functions were measured using a perineometer. Hip muscle strength was measured using a Smart KEMA tension sensor. The relationship between female sexual function and PFM function and hip muscle strength was assessed using Pearson correlation coefficients and multiple regression analyses with forward selection. MAIN OUTCOME MEASURES: PISQ score, PFM functions (strength and endurance), and strength of hip extensor, abductor, and adductor were the main outcome measures. RESULTS: For the behavioral/emotive domain in the PISQ, hip extensor strength (r = 0.452), PFM strength (r = 0.441), PFM endurance (r = 0.362), and hip adductor strength (r = 0.324) were significantly correlated and hip extensor strength emerged in multiple regression. For the physical domain in the PISQ, hip abductor strength (r = 0.417), PFM endurance (r = 0.356), hip adductor strength (r = 0.332), and PFM strength (r = 0.322) were significantly correlated and hip abductor strength entered in multiple regression. For partner-related domain in the PISQ, hip adductor (r = 0.386) and abductor strength (r = 0.314) were significantly correlated and hip adductor strength appeared in multiple regression. For the PISQ total score, hip extensor strength (r = 0.484), PFM endurance (r = 0.470), hip adductor strength (r = 0.424), hip abductor strength (r = 0.393), and PFM strength (r = 0.387) were significantly correlated and hip extensor strength and PFM endurance emerged in multiple regression. CONCLUSION: The female sexual function could be related to not only PFM functions but also hip muscle strength in women with SUI. Hwang UJ, Lee MS, Jung SH, Ahn SH, Kwon OY. Relationship Between Sexual Function and Pelvic Floor and Hip Muscle Strength in Women With Stress Urinary Incontinence. Sex Med 2021;9:100325.

Prognosis of papillary thyroid carcinoma in relation to preoperative subclinical hypothyroidism.

INTRODUCTION: It has been established that thyroid-stimulating hormone (TSH) stimulates the growth and development of thyroid malignancy, and a higher serum TSH level is associated with the incidence of thyroid cancer and an advanced tumour stage. This study aimed to evaluate the association of preoperative subclinical hypothyroidism with the prognosis of papillary thyroid cancer (PTC). METHODS: A total of 466 patients who underwent surgery for PTC between December 2006 and June 2009 were enrolled. Among them, 44 patients had subclinical hypothyroidism, while 422 did not have subclinical hypothyroidism, as diagnosed using the preoperative thyroid function test. We compared the recurrence rate and association with clinicopathological features in the two groups. RESULTS: The median patient age was 46.9 years (17-74 years). There were 420 female and 46 male patients. The median follow-up duration was 81.4 months. There were no statistical differences between the two groups with respect to age, sex, tumour size, extrathyroidal extension, multifocality, lymph node metastasis, TNM stages, recurrence and disease-free survival, despite a significant difference in the average TSH concentrations of the two groups. CONCLUSIONS: Our results suggest that preoperative subclinical hypothyroidism was not associated with tumour aggressiveness and recurrence in PTC.

A natural infection by the red sea bream iridovirus-type Megalocytivirus in the golden mandarin fish Siniperca scherzeri.

An outbreak of a Megalocytivirus infection was found in the golden mandarin fish Siniperca scherzeri during September and October 2016, in Korea. Phylogeny and genetic diversity based on the major capsid protein (MCP) and adenosine triphosphatase (ATPase) genes showed a new strain. Designated as GMIV, this strain derived from the golden mandarin fish was suggested to belong to the red sea bream iridovirus (RSIV)-subgroup I. Additionally, this train clustered with the ehime-1 strain from red sea bream Pagrus major in Japan and was distinguished from circulating isolates (RSIV-type subgroup II and turbot reddish body iridovirus [TRBIV] type) in Korea. The infection level, evaluated by qPCR, ranged from 8.18 × 102 to 7.95 × 106  copies/mg of tissue individually, suggesting that the infected fish were in the disease-transmitting stage. The diseased fish showed degenerative changes associated with cytomegaly in the spleen as general sign of Megalocytivirus infection. The results confirm that the RSIV-type Megalocytivirus might have crossed the environmental and species barriers to cause widespread infection in freshwater fish.

Predictive Factors of Renal Adaptation After Nephrectomy in Kidney Donors.

BACKGROUND: Despite compensatory hyperfiltration in remaining nephrons following donor nephrectomy, some donors show impaired renal adaptation and low estimated glomerular filtration rate (eGFR). We investigated the factors predicting early renal adaptation after nephrectomy and identified kidney donors at risk of inadequate renal adaptation. METHODS: A total of 265 living kidney donors from 2010 to 2013 were retrospectively analyzed. Renal function was serially followed for 6 months after the operation. Regression analyses were performed to identify the independent predictors of low eGFR (eGFR <60 mL/min/1.73 m2) and impaired renal adaptation (%Modification of Diet in Renal Disease [MDRD] <66% of baseline eGFR). RESULTS: A total of 148 donors belonged to the low eGFR group, and changes in eGFR (ΔeGFR) at postoperative (PO) 1 day and 1 month were identified as independent predictors of low eGFR. Impaired renal adaptation was related to age, ΔeGFR PO 2-3 days, and ΔeGFR PO 1 month. Early renal adaptation was associated with age, male gender, and residual kidney computerized tomography angiography (CTA) volume. The best sensitivity and specificity were obtained with a cutoff value of ΔeGFR 31 at PO 1 day and 1 month for predicting low eGFR and with a value of ΔeGFR 27 at PO 2-3 days and 1 month for predicting impaired renal adaptation. CONCLUSIONS: Our study showed that the degree of early renal adaptation determines subsequent renal function in kidney donors. Closer monitoring and management may be required in old or male donors with small residual CTA kidney volume as well as donors with persistent ΔeGFR >27 within 1 month of nephrectomy.

Comparison of shoulder strength in males with and without myofascial trigger points in the upper trapezius.

BACKGROUND: This study was conducted in order to compare the strength of scapular elevator and shoulder abductor with and without restricted scapular elevation between male subjects with and without myofascial trigger points in the upper trapezius. METHODS: In total, 15 male subjects with myofascial trigger points, and 15age- and weight-matched male subjects without myofascial trigger points in the upper trapezius. Each subject was measured in the strength of maximum isometric scapular elevation and shoulder abduction with and without restricted scapular elevation. Maximum isometric contractions were measured using the Smart KEMA strength measurement system. Independent t-tests were used to compare shoulder strength values between the myofascial trigger points and non- myofascial trigger points groups. FINDING: The results showed that shoulder abductor strength in the group with myofascial trigger points (5.64kgf) was significantly lower than in the group without myofascial trigger points (11.96kgf) when scapular elevation was restricted (p<0.05). However, there was no significant difference in the strength of the scapular elevator or shoulder abductor between groups (p>0.05). INTERPRETATION: These findings suggest that decreased strength in the shoulder abductor with restricted scapular elevation should be considered in evaluating and treating individuals with myofascial trigger points of the upper trapezius.

A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance).

BACKGROUND: This multicenter, phase II trial tested the tolerability and efficacy of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma (FL). PATIENTS AND METHODS: Patients with grade 1-3a FL, stage 3-4 or bulky stage 2, FL international prognostic index (FLIPI) 0-2, and no prior therapy were eligible to receive rituximab 375 mg/m2 weekly during cycle 1 and day 1 of cycles 4, 6, 8, and 10, plus lenalidomide 20-25 mg on days 1-21 for twelve 28-day cycles. The primary objectives were to evaluate response rates [complete (CR) and overall] and time to progression. Secondary objectives included toxicity, response according to polymorphisms in FcgR2A and FcgR3A, and changes in circulating pro-angiogenic cells. RESULTS: From October 2010 to September 2011, 66 patients were enrolled. Median age was 53 years, 34 were female, 15 had bulky disease, 21 were FLIPI 0-1, 43 FLIPI 2, and 2 FLIPI 3. One patient withdrew before receiving treatment. Fifty-one patients completed 12 cycles of lenalidomide. Reasons for discontinuation included withdrawal (n = 6), adverse events (n = 6), progression (n = 2). Grade 3-4 hematologic toxicity included neutropenia (21%), lymphopenia (9%), and thrombocytopenia (2%), infection (11%), and rash (8%). Grade 1-2 toxicity included fatigue (78%), diarrhea (37%), rash (32%), and febrile neutropenia in one patient. The overall response rate was 95%; the CR rate was 72% (95% confidence interval, 60% to 83%). With a median follow-up of 5 years, the 2- and 5-year progression-free survival were 86% and 70%, respectively, and the 5-year overall survival was 100%. There was no association between CR rate or PFS and FLIPI, histological grade, bulky disease, FcgR2A/FcgR3A polymorphism, or change in circulating endothelial cell/hematopoietic progenitor cell. CONCLUSION: Lenalidomide plus rituximab was associated with low rates of grade 3-4 toxicity, yielded a CR rate and PFS similar to chemotherapy-based treatment and may represent a reasonable alternative to immunochemotherapy in previously untreated FL. CLINICALTRIALS.GOV IDENTIFIER: NCT01145495.

The clonal origins of leukemic progression of myelodysplasia.

The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.

Radiofrequency ablation and transarterial chemoembolisation as first-line treatment for recurrent hepatocellular carcinoma or isolated intrahepatic recurrent hepatocellular carcinoma in transplanted livers.

AIM: To evaluate the efficacy of radiofrequency ablation (RFA) and transarterial chemoembolisation (TACE) as a first-line treatment for isolated intrahepatic recurrent hepatocellular carcinoma (IIR-HCC) after liver transplantation (LT). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. Between January 2005 and January 2015, 588 consecutive patients underwent LT for the treatment of HCC. Among them, 27 patients with IIR-HCCs after LT who were treated with RFA (n=6) or TACE (n=21) as a first-line treatment were retrospectively included in this study. Disease-free and overall survival rates were estimated using the Kaplan-Meier method. Risk factors affecting these outcomes were assessed with Cox regression models. RESULTS: Except for the total number of recurrent tumours and time-to-tumour recurrence after LT, baseline characteristics were not significantly different between the groups. The 2-year disease-free survival rates for RFA and TACE (20% versus 14%, respectively; p=0.180) and 4-year overall survival rates (33% versus 25%, respectively; p=0.065) were not significantly different between groups. In addition, the types of treatment were not associated with disease-free or overall survival in multivariate analyses. CONCLUSION: TACE may be an effective treatment comparable to RFA in patients with IIR-HCC after LT when RFA is not feasible.

Non-alcoholic fatty liver diseases and risk of colorectal neoplasia.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with colorectal neoplasia. Yet, NAFLD ranges from simple steatosis to steatohepatitis with advanced fibrosis. AIM: To investigate the risk of colorectal neoplasia according to the presence and severity of NAFLD. METHODS: A total of 26 540 asymptomatic adults who underwent same day first-time colonoscopy and abdominal ultrasonography as a health check-up programme were analysed. NAFLD was diagnosed by ultrasonography. Advanced colorectal neoplasia was defined as an invasive cancer or adenoma that was at least 10 mm in diameter, had high-grade dysplasia, or had villous histological characteristics or any combination thereof. RESULTS: NAFLD patients had a higher prevalence of any colorectal neoplasia (38.0% vs. 28.9%) and advanced colorectal neoplasia (2.8% vs. 1.9%) compared to those without NAFLD. In a multivariable model adjusted for age, sex, smoking, alcohol, body mass index, first-degree family history of colorectal cancer, aspirin use and metabolic factors, the odd ratios comparing patients with NAFLD to those without were 1.10 [95% confidence interval (CI): 1.03-1.17] for any colorectal neoplasia and 1.21 (95% CI: 0.99-1.47) for advanced colorectal neoplasia. When NAFLD patients were further stratified according to the non-invasive parameters of liver disease severity, the risk of any colorectal neoplasia or advanced colorectal neoplasia was higher for those with severe liver diseases than those with mild liver diseases. CONCLUSIONS: The presence and severity of NAFLD were closely associated with any colorectal neoplasia and advanced colorectal neoplasia, suggesting that clinicians should be aware of the increased risk of colorectal neoplasia in patients with NAFLD.

Outbreak of hirame rhabdovirus infection in cultured spotted sea bass Lateolabrax maculatus on the western coast of Korea.

In this study, we determined the cause of a disease outbreak in spotted sea bass, Lateolabrax maculatus reared in culture cages on the western coast of Korea in 2013. The major signs in the diseased fish exhibited were haemorrhaging on the membranes of the abdomen, gastrointestinal organs and opercular gills, as well as an enlarged spleen. No external morphological signs of infection were visible, except for a darkening in colour. No parasites or pathological bacteria were isolated from the diseased fish; however, epithelioma papulosum cyprini (EPC) cells inoculated with tissue homogenates from the diseased fish showed cytopathic effects (CPEs). Virus particles in the EPC cells were bullet-shaped, 185-225 nm long and 70-80 nm wide, characteristic of Rhabdoviridae. Polymerase chain reaction analyses of homogenized tissues from the diseased fish and supernatants of cell cultures with CPEs indicated specific, 553-bp-long fragments corresponding to the matrix protein gene of the hirame rhabdovirus (HIRRV). Phylogenetically, the HIRRV phosphoprotein gene of spotted sea bass was more closely related to phosphoproteins from Chinese and Polish HIRRV strains than from other Korean strains. To our knowledge, this is the first report of HIRRV infection in cultured spotted sea bass.

Measuring the effect of femoral malrotation on knee joint biomechanics for total knee arthroplasty using computational simulation.

OBJECTIVES: Malrotation of the femoral component can result in post-operative complications in total knee arthroplasty (TKA), including patellar maltracking. Therefore, we used computational simulation to investigate the influence of femoral malrotation on contact stresses on the polyethylene (PE) insert and on the patellar button as well as on the forces on the collateral ligaments. MATERIALS AND METHODS: Validated finite element (FE) models, for internal and external malrotations from 0° to 10° with regard to the neutral position, were developed to evaluate the effect of malrotation on the femoral component in TKA. Femoral malrotation in TKA on the knee joint was simulated in walking stance-phase gait and squat loading conditions. RESULTS: Contact stress on the medial side of the PE insert increased with internal femoral malrotation and decreased with external femoral malrotation in both stance-phase gait and squat loading conditions. There was an opposite trend in the lateral side of the PE insert case. Contact stress on the patellar button increased with internal femoral malrotation and decreased with external femoral malrotation in both stance-phase gait and squat loading conditions. In particular, contact stress on the patellar button increased by 98% with internal malrotation of 10° in the squat loading condition. The force on the medial collateral ligament (MCL) and the lateral collateral ligament (LCL) increased with internal and external femoral malrotations, respectively. CONCLUSIONS: These findings provide support for orthopaedic surgeons to determine a more accurate femoral component alignment in order to reduce post-operative PE problems.Cite this article: K-T. Kang, Y-G. Koh, J. Son, O-R. Kwon, C. Baek, S. H. Jung, K. K. Park. Measuring the effect of femoral malrotation on knee joint biomechanics for total knee arthroplasty using computational simulation. Bone Joint Res 2016;5:552-559. DOI: 10.1302/2046-3758.511.BJR-2016-0107.R1.

Changes in tumour expression of programmed death-ligand 1 after neoadjuvant concurrent chemoradiotherapy in patients with squamous oesophageal cancer.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression has been suggested as a potential predictive biomarker of response to anti-PD-1/PD-L1 therapy. In this study, we investigated whether the expression of PD-L1 in tumour cells is affected by neoadjuvant concurrent chemoradiotherapy (CCRT) or chemotherapy in oesophageal squamous cell carcinoma. PATIENTS AND METHODS: Between 2004 and 2014, we collected the medical records of locally advanced oesophageal cancer patients consecutively diagnosed and treated with neoadjuvant CCRT or chemotherapy, followed by curative resection. PD-L1 expression in acquired tissue specimens was evaluated by immunohistochemistry using the H-score. The changes in PD-L1 expression between paired samples were evaluated and we also analysed PD-L1 expression in surgical tumour specimens to evaluate its prognostic role. RESULTS: Twenty-eight paired tumour tissues that were acquired before and after neoadjuvant therapy were available: 19 patients with CCRT and 9 with chemotherapy before complete oesophagectomy. The PD-L1 H-score increased significantly from baseline tumour tissues to surgical tumour tissues after neoadjuvant CCRT (P = 0.007, median H-score from 28 to 52), whereas it decreased significantly after neoadjuvant chemotherapy (P = 0.048, median H-score from 53 to 22). In a total of 73 patients, including 45 additional cases for the prognosis analysis, patients with higher PD-L1 H-scores (≥ 20) had poorer overall survival (median 16.7 versus 32.9 months, P = 0.02) than those with lower H-scores (<20). CONCLUSIONS: PD-L1 expression in tumour cells increased in oesophageal cancer patients who received neoadjuvant CCRT. Further studies with more cases are necessary to validate these findings.

Clonal dynamics in a single AML case tracked for 9 years reveals the complexity of leukemia progression.

Most types of cancers are made up of heterogeneous mixtures of genetically distinct subclones. In particular, acute myeloid leukemia (AML) has been shown to undergo substantial clonal evolution over the course of the disease. AML tends to harbor fewer mutations than solid tumors, making it challenging to infer clonal structure. Here, we present a 9-year, whole-exome sequencing study of a single case at 12 time points, from the initial diagnosis until a fourth relapse, including 6 remission samples in between. To the best of our knowledge, it covers the longest time span of any data set of its kind. We used these time series data to track the hierarchy and order of variant acquisition, and subsequently analyzed the evolution of somatic variants to infer clonal structure. From this, we postulate the development and extinction of subclones, as well as their anticorrelated expansion via varying drug responses. In particular, we show that new subclones started appearing after the first complete remission. The presence and absence of different subclones during remission and relapses implies differing drug responses among subclones. Our study shows that time series analysis contrasting remission and relapse periods provides a much more comprehensive view of clonal structure and evolution.

Heparan sulfation is essential for the prevention of cellular senescence.

Cellular senescence is considered as an important tumor-suppressive mechanism. Here, we demonstrated that heparan sulfate (HS) prevents cellular senescence by fine-tuning of the fibroblast growth factor receptor (FGFR) signaling pathway. We found that depletion of 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2), a synthetic enzyme of the sulfur donor PAPS, led to premature cell senescence in various cancer cells and in a xenograft tumor mouse model. Sodium chlorate, a metabolic inhibitor of HS sulfation also induced a cellular senescence phenotype. p53 and p21 accumulation was essential for PAPSS2-mediated cellular senescence. Such senescence phenotypes were closely correlated with cell surface HS levels in both cancer cells and human diploid fibroblasts. The determination of the activation of receptors such as FGFR1, Met, and insulin growth factor 1 receptor ß indicated that the augmented FGFR1/AKT signaling was specifically involved in premature senescence in a HS-dependent manner. Thus, blockade of either FGFR1 or AKT prohibited p53 and p21 accumulation and cell fate switched from cellular senescence to apoptosis. In particular, desulfation at the 2-O position in the HS chain contributed to the premature senescence via the augmented FGFR1 signaling. Taken together, we reveal, for the first time, that the proper status of HS is essential for the prevention of cellular senescence. These observations allowed us to hypothesize that the FGF/FGFR signaling system could initiate novel tumor defenses through regulating premature senescence.

A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer.

BACKGROUND: The purpose of this randomised phase III trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitor, to XELIRI/FOLFIRI chemotherapy regimens confers a clinical benefit to patients with previously treated metastatic colorectal cancer. METHODS: We undertook a double-blind, placebo-controlled phase III trial of 269 patients previously treated for metastatic colorectal cancer and enrolled in 5 centres in South Korea. Patients were randomly assigned (1:1) to one of the following groups: FOLFIRI/XELIRI plus simvastatin (40 mg) or FOLFIRI/XELIRI plus placebo. The FOLFIRI regimen consisted of irinotecan at 180 mg m(-2) as a 90-min infusion, leucovorin at 200 mg m(-2) as a 2-h infusion, and a bolus injection of 5-FU 400 mg m(-2) followed by a 46-h continuous infusion of 5-FU at 2400 mg m(-2). The XELIRI regimen consisted of irinotecan at 250 mg m(-2) as a 90-min infusion with capecitabine 1000 mg m(-2) twice daily for 14 days. The primary end point was progression-free survival (PFS). Secondary end points included response rate, duration of response, overall survival (OS), time to progression, and toxicity. RESULTS: Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median PFS was 5.9 months (95% CI, 4.5-7.3) in the XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4-8.6) in the XELIRI/FOLFIRI plus placebo group (P=0.937). No significant difference was observed between the two groups with respect to OS (median, 15.9 months (simvastatin) vs 19.9 months (placebo), P=0.826). Grade⩾3 nausea and anorexia were noted slightly more often in patients in the simvastatin arm compared with with the placebo arm (4.5% vs 0.7%, 3.0% vs 0%, respectively). CONCLUSIONS: The addition of 40 mg simvastatin to the XELIRI/FOLFIRI regimens did not improve PFS in patients with previously treated metastatic colorectal cancer nor did it increase toxicity.

Effects of Oxide Layer on the Bonding Strength of Ni-Cr Alloys with Porcelain Ceramics.

The metal-ceramic crown restoration was the most actively used at esthetic restoration for its convenience of forming. Due to constant rise of gold price, non-precious metal such as Ni-Cr alloy have been widely used as metal-ceramic restorations. For easy casting and lower melting point Be was added as minor component to Ni-Cr for a long time, but the use of Be was regulated to deteriorate to human lung. In this study, Ni-Cr specimens containing Be (T-3, Ticonium, USA) and non-Be (Bellabond Plus, BEGO, Germany) were fabricated and by heat treatments at 800-1050 0C oxide layer was formed for subsequent bonding to porcelain ceramics. By heat treatment of the non-Be specimens at high temperature more thick oxide layer was formed and showed lower bonding strength due to the debonding at oxide layers. But in the Be-containing specimens debonding was occurred at porcelain layer so that they showed higher bonding strength. So by heat treatment of non-Be specimens at vacuum condition rather thinner oxide film could be formed so that showed higher coupling strength due to the debonding at porcelain layers than oxide layers.

Investigation of hydrodynamic parameters in a draft tube reactor using radioisotope based techniques and conventional method.

In this study, various techniques were attempted to investigate flow dynamics in the enclosed reactor and the results from the techniques were compared. Radioactive particle tracking (RPT) and industrial single photon emission computed tomography (SPECT) were carried out and the circulation times from them showed a deviation of 17.5%. The circulation time of the RPT was longer than that of SPECT, and it is speculated that the physical dimension of the/ fabricated radioactive particle creates the discrepancy. Particle image velocimetry (PIV) measurements and computational fluid dynamic (CFD) simulations were conducted. The velocity patterns from them were similar to each other in the entire reactor region except near the propeller installed at the bottom of the reactor.