bluuebunny/crossref_metadata_2025 huggingface dataset:
Raf Kinase Inhibitor Protein RKIP Enhances Signaling by Glycogen Synthase Kinase-3β
Authors: Al-Mulla Fahd , Bitar Milad S. , Al-Maghrebi May , Behbehani Abdulla I. , Al-Ali Waleed , Rath Oliver , Doyle Brendan , Tan Kit Yee , Pitt Andrew , Kolch Walter
Published: February 2011

Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor κB signaling that represses tumor invasion and metastasis. Glycogen synthase kinase-3β (GSK3β) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. Here, we show that RKIP binds GSK3 proteins and maintains GSK3β protein levels and its active form. Depletion of RKIP augments oxidative stress–mediated activation of the p38 mitogen activated protein kinase, which, in turn, inactivates GSK3β by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3β inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and β-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3β expression. These findings reveal the RKIP/GSK3 axis as both a potential therapeutic target and a prognosis-based predictor of cancer progression. Cancer Res; 71(4); 1334–43. ©2011 AACR.
Altered TGF-β Signaling in a Subpopulation of Human Stromal Cells Promotes Prostatic Carcinogenesis
Authors: Franco Omar E. , Jiang Ming , Strand Douglas W. , Peacock James , Fernandez Suzanne , Jackson Roger S. , Revelo Monica P. , Bhowmick Neil A. , Hayward Simon W.
Published: February 2011

Carcinoma-associated fibroblasts (CAF) play a critical role in malignant progression. Loss of TGF-β receptor II (TGFβR2) in the prostate stroma is correlated with prostatic tumorigenesis. To determine the mechanisms by which stromal heterogeneity because of loss of TGFβR2 might contribute to cancer progression, we attenuated transforming growth factor beta (TGF-β) signaling in a subpopulation of immortalized human prostate fibroblasts in a model of tumor progression. In a tissue recombination model, loss of TGFβR2 function in 50% of the stromal cell population resulted in malignant transformation of the nontumorigenic human prostate epithelial cell line BPH1. Mixing fibroblasts expressing the empty vector and dominant negative TGFβR2 increased the expression of markers of myofibroblast differentiation [coexpression of vimentin and alpha smooth muscle actin (αSMA)] through elevation of TGF-β1 and activation of the Akt pathway. In combination, these two populations of stromal cells recapitulated the tumor inductive activity of CAFs. TGFβR2 activity in mixed stromal cell populations cultured in vitro caused secretion of factors that are known to promote tumor progression, including TGF-β1, SDF1/CXCL12, and members of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families. In vivo, tissue recombination of fibroblasts overexpressing TGF-β1 and SDF1/CXCL12 not only induced transformation of BPH1 cells, but also promoted a robust growth of highly invasive cells, similar to effects produced by CAFs. While the precise nature and/or origin of the particular stromal cell populations in vivo remain unknown, these findings strongly link heterogeneity in TGF-β signaling to tumor promotion by tumor stromal cells. Cancer Res; 71(4); 1272–81. ©2011 AACR.
Fusion between Intestinal Epithelial Cells and Macrophages in a Cancer Context Results in Nuclear Reprogramming
Authors: Powell Anne E. , Anderson Eric C. , Davies Paige S. , Silk Alain D. , Pelz Carl , Impey Soren , Wong Melissa H.
Published: February 2011

The most deadly phase in cancer progression is attributed to the inappropriate acquisition of molecular machinery leading to metastatic transformation and spread of disease to distant organs. Although it is appreciated that metastasis involves epithelial–mesenchymal interplay, the underlying mechanism defining this process is poorly understood. Specifically, how cancer cells evade immune surveillance and gain the ability to navigate the circulatory system remains a focus. One possible mechanism underlying metastatic conversion is fusion between blood-derived immune cells and cancer cells. While this notion is a century old, in vivo evidence that cell fusion occurs within tumors and imparts genetic or physiologic changes remains controversial. We have previously demonstrated in vivo cell fusion between blood cells and intestinal epithelial cells in an injury setting. Here, we hypothesize that immune cells, such as macrophages, fuse with tumor cells imparting metastatic capabilities by transferring their cellular identity. We used parabiosis to introduce fluorescent-labeled bone marrow-derived cells to mice with intestinal tumors, finding that fusion between circulating blood-derived cells and tumor epithelium occurs during the natural course of tumorigenesis. Moreover, we identify the macrophage as a key cellular partner for this process. Interestingly, cell fusion hybrids retain a transcriptome identity characteristic of both parental derivatives, while also expressing a unique subset of transcripts. Our data supports the novel possibility that tumorigenic cell fusion may impart physical behavior attributed to migratory macrophages, including navigation of circulation and immune evasion. As such, cell fusion may represent a promising novel mechanism underlying the metastatic conversion of cancer cells. Cancer Res; 71(4); 1497–505. ©2011 AACR.
MTGR1 Is Required for Tumorigenesis in the Murine AOM/DSS Colitis-Associated Carcinoma Model
Authors: Barrett Caitlyn W. , Fingleton Barbara , Williams Amanda , Ning Wei , Fischer Melissa A. , Washington Mary K. , Chaturvedi Rupesh , Wilson Keith T. , Hiebert Scott W. , Williams Christopher S.
Published: February 2011

Myeloid Translocation Gene, Related-1 (MTGR1) CBFA2T2 is a member of the Myeloid Translocation Gene (MTG) family of transcriptional corepressors. The remaining two family members, MTG8 (RUNX1T1) and MTG16 (CBFA2T3) are identified as targets of chromosomal translocations in acute myeloid leukemia (AML). Mtgr1−/− mice have defects in intestinal lineage allocation and wound healing. Moreover, these mice show signs of impaired intestinal stem cell function. Based on these phenotypes, we hypothesized that MTGR1 may influence tumorigenesis arising in an inflammatory background. We report that Mtgr1−/− mice were protected from tumorigenesis when injected with azoxymethane (AOM) and then subjected to repeated cycles of dextran sodium sulfate (DSS). Tumor cell proliferation was comparable, but Mtgr1−/− tumors had significantly higher apoptosis rates. These phenotypes were dependent on epithelial injury, the resultant inflammation, or a combination of both as there was no difference in aberrant crypt foci (ACF) or tumor burden when animals were treated with AOM as the sole agent. Gene expression analysis indicated that Mtgr1−/− tumors had significant upregulation of inflammatory networks, and immunohistochemistry (IHC) for immune cell subsets revealed a marked multilineage increase in infiltrates, consisting predominately of CD3+ and natural killer T (NKT) cells as well as macrophages. Transplantation of wild type (WT) bone marrow into Mtgr1−/− mice, and the reciprocal transplant, did not alter the phenotype, ruling out an MTGR1 hematopoietic cell-autonomous mechanism. Our findings indicate that MTGR1 is required for efficient inflammatory carcinogenesis in this model, and implicate its dysfunction in colitis-associated carcinoma. This represents the first report functionally linking MTGR1 to intestinal tumorigenesis. Cancer Res; 71(4); 1302–12. ©2011 AACR.
Clinical Validation of Colorectal Cancer Biomarkers Identified from Bioinformatics Analysis of Public Expression Data
Authors: Jung Yeonjoo , Lee Sanghyuk , Choi Hyung-Seok , Kim Soon-Nam , Lee Eunyoung , Shin Youngah , Seo Jihae , Kim Bumjin , Jung Yeonhwa , Kim Wan Kyu , Chun Ho-Kyung , Lee Woo Yong , Kim Jaesang
Published: February 2011

Purpose: Identification of novel biomarkers of cancer is important for improved diagnosis, prognosis, and therapeutic intervention. This study aimed to identify marker genes of colorectal cancer (CRC) by combining bioinformatics analysis of gene expression data and validation experiments using patient samples and to examine the potential connection between validated markers and the established oncogenes such as c-Myc and K-ras.

Experimental Design: Publicly available data from GenBank and Oncomine were meta-analyzed leading to 34 candidate marker genes of CRC. Multiple case-matched normal and tumor tissues were examined by RT-PCR for differential expression, and 9 genes were validated as CRC biomarkers. Statistical analyses for correlation with major clinical parameters were carried out, and RNA interference was used to examine connection with major oncogenes.

Results: We show with high confidence that 9 (ECT2, ETV4, DDX21, RAN, S100A11, RPS4X, HSPD1, CKS2, and C9orf140) of the 34 candidate genes are expressed at significantly elevated levels in CRC tissues compared to normal tissues. Furthermore, high-level expression of RPS4X was associated with nonmucinous cancer cell type and that of ECT2 with lack of lymphatic invasion while upregulation of CKS2 was correlated with early tumor stage and lack of family history of CRC. We also demonstrate that RPS4X and DDX21 are regulatory targets of c-Myc and ETV4 is downstream to K-ras signaling.

Conclusions: We have identified multiple novel biomarkers of CRC. Further analyses of their function and connection to signaling pathways may reveal potential value of these biomarkers in diagnosis, prognosis, and treatment of CRC. Clin Cancer Res; 17(4); 700–9. ©2011 AACR.
Markers of Pancreatic Cancer: Working Toward Early Detection
Authors: Goggins Michael
Published: February 2011

Because early detection of pancreatic cancer is the best way to cure this disease, investigators continue to try to identify accurate markers of early pancreatic cancer. Because early-stage pancreatic cancer is generally asymptomatic, the only reliable way to detect it is by targeting individuals at increased risk for pancreatic screening. Clin Cancer Res; 17(4); 635–7. ©2011 AACR.
Low-Dose Valproic Acid Enhances Radiosensitivity of Prostate Cancer through Acetylated p53-Dependent Modulation of Mitochondrial Membrane Potential and Apoptosis
Authors: Chen Xufeng , Wong Jeffrey Y.C. , Wong Patty , Radany Eric H.
Published: February 2011

Histone deacetylase inhibitors (HDI) have shown promise as candidate radiosensitizers for many types of cancers, including prostate cancer. However, the mechanisms of action are not well understood. In this study, we show in prostate cancer cells that valproic acid (VPA) at low concentrations has minimal cytotoxic effects yet can significantly increase radiation-induced apoptosis. VPA seems to stabilize a specific acetyl modification (lysine 120) of the p53 tumor suppressor protein, resulting in an increase in its proapoptotic function at the mitochondrial membrane. These effects of VPA are independent of any action of the p53 protein as a transcription factor in the nucleus, since these effects were also observed in native and engineered prostate cancer cells containing mutant forms of p53 protein having no transcription factor activity. Transcription levels of p53-related or Bcl-2 family member proapoptotic proteins were not affected by VPA exposure. The results of this study suggest that, in addition to nuclear-based pathways previously reported, HDIs may also result in radiosensitization at lower concentrations via a specific p53 acetylation and its mitochondrial-based pathway(s). Mol Cancer Res; 9(4); 448–61. ©2011 AACR.
Urodynamic Impact of Acute Urinary Retention in Patients with Benign Prostatic Hyperplasia: A 2-Year Follow-Up after Transurethral Resection of the Prostate
Authors: Wagenlehner Florian M.E. , Bescherer Knut , Wagenlehner Christine , Zellner Michael , Weidner Wolfgang , Naber Kurt G.
Published: February 2011

Introduction: Benign prostatic hyperplasia (BPH) may ultimately result in acute urinary retention (AUR). This study was performed to assess the impact of transurethral resection of the prostate (TURP) on urodynamic parameters in patients with BPH using pre- and postoperative pressure-flow studies (PFS) and compare those between patients with and without preoperative AUR. Patients and Methods: 78 patients underwent TURP because of symptoms due to BPH and were evaluated preoperatively and at follow-up after a mean ± SD of 27 ± 11.5 months by the International Prostate Symptom Score and PFS. Results: 32% of patients were admitted with AUR. The clinical and principal urodynamic parameters exhibited statistically significant improvement reaching normal values after TURP in most patients. Comparing patients with and without AUR, the bladder compliance significantly increased (p = 0.0013) from the preoperative period to follow-up only in patients with preoperative AUR. The minimal opening pressure decreased significantly more (p = 0.0077) from the preoperative period to follow-up in the non-AUR group. Patients older than 80 years and younger patients showed comparable results. Conclusions: TURP leads to a sustained and age-independent improvement of clinically relevant PFS parameters in patients with BPH. Patients with preoperative AUR had comparable symptomatic, but an impaired urodynamic outcome compared to patients without AUR.
Bone-Marrow-Derived Mesenchymal Stem Cell Transplantation Enhances Closing Pressure and Leak Point Pressure in a Female Urinary Incontinence Rat Model
Authors: Kim Sun-Ouck , Na Hee Sam , Kwon Dongdeuk , Joo Soo Yeon , Kim Hyung Suck , Ahn Youngkeun
Published: February 2011

Purpose: The purpose of this study was to determine whether periurethral injection of allogenic mesenchymal stem cells (MSCs) could increase the leak point pressure (LPP) in a rat model of stress urinary incontinence. Materials and Methods: Female Sprague-Dawley rats (230–240 g, n = 30) were divided into 3 groups: sham operation (group C), saline-treated (group S) and MSC-treated (group M). Bilateral pudendal nerve dissection followed by normal saline or MSC injection on both sides of the urethra was done. LPP and closing pressure (CP) testing was performed after the treatment. The specific markers for smooth muscle cells in the transplantation sites of the urethra were determined. Results: Both the LPP and CP were significantly lower in group S than controls. However, these were restored to the control values in group M (p < 0.05). The LPPs of groups C, S and M were 29.1 ± 2.1, 22.0 ± 2.2 and 43.1 ± 3.2 cm H2O, respectively. The CPs of groups C, S and M were 27.1 ± 3.1, 21.1 ± 3.2, and 32.1 ± 2.1 cm H2O, respectively. The injected MSCs stained positive for muscle-specific markers. Conclusion: This study suggests that MSCs might differentiate into muscle lineage cells and may contribute to the repair of damaged muscle tissue.
Does a Pre-Operative Urodynamic Diagnosis of Bladder Outflow Obstruction Improve Outcomes from Palliative Transurethral Prostatectomy?
Authors: Gnanapragasam V.J. , Leonard A.
Published: February 2011

Objective: Palliative transurethral prostatectomy (TURP) is the mainstay of treatment for lower urinary tract symptoms, (LUTS) in men with prostate cancer. Functional outcomes, however, can often be unsatisfactory. Here the value of preoperative urodynamics was investigated in these men. Methods: A retrospective review was conducted of41men with prostate cancer and LUTS who were investigated by urodynamics prior to TURP. All were treated solely by primary androgen deprivation. 19 men with urodynamic proven bladder outflow obstruction (BOO) proceeded to palliative TURP. Results: Of the 41 men investigated by cystometry, the urodynamic diagnosis was BOO in 12 (29%) men, detrusor overactivity in 12 (29%) men with 7 (17%) having both diagnoses. 6 (15%) men were found to have underactive or acontractile detrusors while 4 (10%) had normal studies. In men who proceeded to TURP, all demonstrated improved flow rates (p = 0.003). At 12 months, 95% were voiding spontaneously with only 1 man requiring permanent re-catheterisation. These results compared very favourably to published outcomes which have not used urodynamics to select men for surgery. Conclusions: Urodynamics may help identify objective BOO prior to palliative TURP. Further prospective trials are justified to assess the role of urodynamics in this context.
Quality of Care Indicators for Muscle-Invasive Bladder Cancer
Authors: Goossens-Laan Catharina A. , Kil Paul J.M. , Roukema Jan A. , Bosch J.L.H. Ruud , De Vries Jolanda
Published: February 2011

Objective: To define a set of quantifiable quality of care indicators (QIs) to measure the standard of care in our institute given to patients with muscle-invasive bladder cancer (MIBC). Patients and Methods: Possible QIs were defined and selected by a multidisciplinary project group from recent literature, guidelines, and/or consensus within the project group. In a retrospective study a baseline for each QI was assessed and compared to a predefined benchmark. Results: Four categories of QIs were selected: (1) care management, (2) accessibility and time management, (3) professional competence, and (4) patient factors. A list of 26 QIs was created. In the retrospective study, it became evident that 22 QIs failed to reach their benchmark, because of (1) an inadequate process of care (n = 5), (2) insufficient care given (n = 14), and (3) data not retrievable in retrospective study design (n = 2). Adjustments were made in the different processes of care in order to improve quality of care. Conclusions: In the face of a complete lack of a QoC registration system for MIBC, we listed 26 quantifiable QIs, to measure QoC in our own institute. Our process of care did not meet 22 of the benchmarks, after which adjustments were made. This QoC registration method is a first step in defining applicable quality of care indicators, for implementation in the clinical practice.
Unusual Bladder Mass in a 14-Year-Old Boy: Bladder Paraganglioma
Authors: De Pasquale V. , Magistrelli A. , Diomedi Camassei F. , Caione P.
Published: February 2011

A 14-year-old boy presenting headache crisis, sweating and palpitation was observed. On ultrasound scan, a 3 × 2.5 cm hypoechoic mass, highly vascularized, was observed arising from the left bladder wall. Magnetic resonance imaging confirmed the mass situated close to the ureteral orifice, with intense peripheral enhancement and a central non-enhanced portion. Left partial cystectomy was performed. Large clear cells, presenting cytoplasmatic granules positive for S100 and chromogranin, were observed at histology. Bladder paraganglioma derives from chromaffin tissue of the sympathic system and it is uncommon in children. The estimated prevalence is very low (0.06% of bladder tumors). Symptomatology is related to the catecholamine production. In pediatrics, prognosis is usually good but long-term follow-up is required.
Correlation of Pathological and Cytological-Cytometric Grading of Transitional Cell Carcinoma of the Urinary Tract
Authors: vom Dorp Frank , Pal Philip , Tschirdewahn S. , Rossi Roberto , Börgermann C. , Schenck Markus , Becker Markus , Szarvas Tibor , Hakenberg Oliver W. , Rübben Herbert
Published: February 2011

Introduction: Cystoscopy and cytology are standard procedures for diagnosis and follow-up of patients with bladder cancer. Urinary cytodiagnosis is a descriptive method for tumor characterization. We correlated histopathologic diagnosis of noninvasive urothelial carcinomas with cytological evaluation and, furthermore, we validated cytology by cytometric analysis. Patients and Methods: 94 patients with a history of bladder cancer were included in the study. 25 patients were negative for tumors, 22 showed pTa G1 carcinomas, 25 had pTaG2 and 22 patients had G3 carcinomas. All patients underwent cytological and cytometric evaluation. Nuclear diameter and circumference were measured for 15 representative nuclei per specimen. Statistical evaluation was performed using Graph Pad Software. Results: Cytology showed excellent tumor detection for G2 and G3 carcinomas, with a sensitivity of 100% combined with a specificity of 100%. Using cytometry, we can significantly distinguish between unsuspicious patients and G1 carcinomas on the one hand and high-grade carcinomas on the other. Furthermore, in 6 of 25 patients (24%) with noninvasive G2 carcinomas, but G3 cytological evaluation, tumor progression occurred. Conclusions: Urinary cytology is an excellent instrument for detection of clinically relevant high-grade bladder cancer. Descriptive alterations of the cytopathology can be validated by objective data using cytometric analysis.
Delayed Detection of Injury to an Ectopic Ureter of a Duplicated Collecting System following Laparoscopic Radical Prostatectomy for Early Organ-Confined Prostate Cancer
Authors: Ghazi A. , Zimmermann R. , Janetschek G.
Published: February 2011

In the era of early detection of organ-confined prostate cancer, guidelines support the fact that many patients will not need an aggressive staging work-up, to avoid unnecessary investigations. This strategy may lead to serious repercussions in rare incidences. We present a rare case of urinary extravasation following laparoscopic radical prostatectomy caused by injury of the upper pole ectopic ureter of an undetected duplex system on 1 side, an injury which is the first of its kind in laparoscopic urology.
GSTT1: A Marker of the Aggressiveness of Bladder Cancer
Authors: Ha Yun-Sok , Yan Chunri , Park Cheol , Yun Seok-Joong , Moon Sung-Kwon , Choi Yung Hyun , Kim Wun-Jae
Published: February 2011

Introduction: Glutathione S-transferases have been implicated in the development of bladder cancer (BC). We investigated the genotype and expression of glutathione S-transferase-mu (GSTM1) and glutathione S-transferase-theta (GSTT1) in BC tissue specimens. Materials and Methods: Tumor samples and matched normal mucosae were obtained from 34 patients. Genomic DNA was used to analyze GSTM1 and GSTT1 genotypes using multiplex polymerase chain reaction. GSTM1 and GSTT1 mRNA levels were measured using real-time reverse transcriptase polymerase chain reaction. Results:GSTM1 mRNA expression was lower in tumor tissues than in matched normal bladder mucosae, whereas GSTT1 mRNA expression was significantly higher. GSTT1 mRNA expression was higher in muscle-invasive BC and high-grade cancers than in non-muscle-invasive BC and lower-grade tumors. Conclusions:GSTT1 is correlated with characteristics of aggressive BC. GSTT1 may play an important role in tumorigenesis and disease progression in patients with BC.
Effects of Bevacizumab on Autocrine VEGF Stimulation in Bladder Cancer Cell Lines
Authors: Videira Paula A. , Piteira A. Rita , Cabral M. Guadalupe , Martins Catarina , Correia Manuela , Severino Paulo , Gouveia Helena , Carrascal Mylène , Almeida Joana F. , Trindade Hélder , Santos Lúcio Lara
Published: February 2011

Introduction: A functional vascular endothelial growth factor A (VEGF-A) autocrine loop is crucial for bladder cancer cell survival. We reasoned that treatment with the anti-VEGF antibody bevacizumab may result either in cell growth prevention or in the cell adaptation to compensate VEGF deprivation. Methods: The cytotoxicity of different levels of bevacizumab and its effect on the gene expression was analyzed in human bladder cancer cell lines. Results: Inhibition of bladder cancer cell proliferation was observed at >2.5 mg/ml of bevacizumab. Non-muscle-invasive bladder cancer cells expressed high concentrations of VEGF-A, and were less susceptible to bevacizumab inhibition. At 0.5 mg/ml (FDA approved concentration) of bevacizumab, cells increase their expression of VEGF-A, VEGF-A receptors and related growth factors. Conclusions: Bevacizumab cytotoxicity is only observed at high concentration, and it is inversely correlated with the basal VEGF-A expression of the bladder cancer cells. This is the first report showing that, at clinical bevacizumab concentrations, cancer cells compensate the VEGF-A blockade, by improving the expression of VEGF-A and related genes, highlighting the need to follow the patient’s adaptation response to bevacizumab treatment.
Effect and Safety of Granulocyte-Monocyte Adsorption Apheresis for Patients with Ulcerative Colitis Positive for Cytomegalovirus in Comparison with Immunosuppressants
Authors: Yoshino Takuya , Nakase Hiroshi , Matsuura Minoru , Matsumura Kayoko , Honzawa Yusuke , Fukuchi Takumi , Watanabe Kenji , Murano Mitsuyuki , Tsujikawa Tomoyuki , Fukunaga Ken , Matsumoto Takayuki , Chiba Tsutomu
Published: February 2011

Background: Cytomegalovirus (CMV) infection exacerbates ulcerative colitis (UC) refractory to immunosuppressive therapies (IMT). However, the underlying UC remained active in some UC patients, despite the fact that CMV-DNA in colonic mucosa became negative after antiviral therapy. Therefore, new therapeutic strategies for UC patients concomitant with CMV infection in mucosa are required. Aims: The aim of this study was to evaluate the effect and safety of granulocyte-monocyte adsorption apheresis (GMA) in UC patients positive for CMV infection after antiviral therapy. Methods: From October 2003 to December 2008, 64 patients with UC refractory to IMT, including steroids and immunomodulators, were enrolled in this retrospective, observational, multicenter study, which was reviewed and approved by the Institutional Review Board of Kyoto University. CMV infection was investigated by 3 methods (histologic examination, CMV antigenemia, and polymerase chain reaction). We investigated the clinical outcomes of GMA and IMT after 2 weeks of treatment with ganciclovir. Results: Thirty-one (48.4%) of 64 patients with UC refractory to IMT were positive for CMV. Of the 31 patients, 4 (12.9%) underwent colectomy. Twenty-seven patients (87.1%) underwent antiviral therapy. Of those 27 patients, 7 achieved remission following antiviral therapy alone. Of the remaining 20 patients who did not achieve remission despite the disappearance of CMV-DNA, 11 and 9 patients were treated with additional GMA (GMA group) and IMT (IMT group), respectively. Of 11 patients (GMA group), 9 achieved remission and 2 underwent colectomy. Out of the remaining 9 patients (IMT group), 4 achieved remission and 5 underwent colectomy. CMV-DNA was not detected in 11 patients after GMA, but it was detected again in all 5 patients of the IMT group who underwent colectomy. The total colectomy rate in UC patients positive for CMV was 35.5% (11/31). In addition, colectomy-free survival in the CMV relapse (+) group was estimated to be 12.9% at 65 months, while that in the CMV relapse (–) group was estimated to be 100% at 60 months. Conclusion: The colectomy ratio tends to be high in refractory UC patients with recurrent CMV reactivation or infection. Therefore, GMA might be a safe and effective treatment for UC patients positive for CMV because it does not induce CMV reactivation.
Variability in the Assessment of ‘Adequate’ Chest Excursion during Simulated Neonatal Resuscitation
Authors: Brugada M. , Schilleman K. , Witlox R.S. , Walther F.J. , Vento M. , te Pas A.B.
Published: February 2011

Background: International neonatal resuscitation guidelines recommend assessing chest excursion when the heart rate is not improving. However, the accuracy in assessing ‘adequate’ chest excursion lacks objectivity. Aim: It was the aim of this study to test the accuracy in the assessment of ‘adequate’ chest excursion by measuring intra- and inter-observer variability of participants during simulated neonatal resuscitation. Methods: Thirty-seven staff members (8 neonatologists, 8 registrars, 21 nurses) of the Neonatal Intensive Care Unit, Leiden University Medical Center, Leiden, The Netherlands, ventilated 2 different intubated, leak-free manikins at 2 attempts, each with a different compliance. Blinded to the manometer, participants could change the peak inflation pressure until chest movement was adequate according to their perception. Inflating pressures were recorded. Results: According to the participants, a median (interquartile range) pressure of 18 cm H2O (16–22) at the first and 18 cm H2O (16–25) at the second attempt were needed to reach adequate chest excursion in the Laerdal manikin. The HAL manikin needed 26 cm H2O (19–31) and 24 cm H2O (22–33), respectively. The inter-observer coefficient of variance was 30% with the Laerdal manikin at both attempts, and 35 and 40% with the HAL manikin, respectively. The intra-observer coefficient of variance was 15% (8–23) with the Laerdal and 13% (9–20) with the HAL manikin. In both manikins and attempts, no significant differences in pressures and variances of pressures between the 3 groups were found. Conclusion: ‘Adequate’ chest excursion is a subjective parameter for guidance of appropriate ventilation during neonatal resuscitation.
Effect of Exercise and Respiratory Training on Clinical Progression and Survival in Patients with Severe Chronic Pulmonary Hypertension
Authors: Grünig Ekkehard , Ehlken Nicola , Ghofrani Ardeschir , Staehler Gerd , Meyer F. Joachim , Juenger Jana , Opitz Christian F. , Klose Hans , Wilkens Heinrike , Rosenkranz Stephan , Olschewski Horst , Halank Michael
Published: February 2011

Background: Even though specific agents for the treatment of patients with pulmonary hypertension (PH) are available, in PH patients, physical capacity and quality of life (QoL) are often restricted and survival is reduced. Objectives: This study prospectively investigated the long-term effects of respiratory and exercise training in patients with severe chronic PH regarding safety, time to clinical worsening and survival. Methods: Fifty-eight consecutive patients with severe PH on stable disease-targeted medication received exercise and respiratory training in hospital for 3 weeks and continued at home. They were prospectively followed for 24 ± 12 months. Primary endpoints were time to clinical worsening and survival. Adverse events and changes in the 6-min walking test, QoL, WHO functional class and gas exchange were secondary endpoints and were evaluated at baseline and at weeks 3 and 15. Results: All patients tolerated the exercise training well without severe adverse events. In week 15, 6-min walking test results were significantly improved compared to baseline (by 84 ± 49 m, p < 0.001), as well as QoL scores, WHO functional class (from 2.9 ± 0.5 to 2.6 ± 0.6, p < 0.01), peak oxygen consumption (from 12.5 ± 3.0 to 14.6 ± 3.9 ml/min/kg, p < 0.001), heart rate at rest (from 75 ± 12 to 61 ± 18 beats/min, p < 0.001) and maximal workload (from 65 ± 21 to 80 ± 25 W, p < 0.001). Survival at 1 and 2 years was 100 and 95%, respectively. Fifteen events occurred during the follow-up. Conclusion: This study indicates that exercise and respiratory training as add-on to medical treatment may improve exercise capacity and QoL, and that they have a good long-term safety in the described setting.
Different Molecular and Structural Adaptations with Eccentric and Conventional Strength Training in Elderly Men and Women
Authors: Mueller Matthias , Breil Fabio Andreas , Lurman Glenn , Klossner Stephan , Flück Martin , Billeter Rudolf , Däpp Christoph , Hoppeler Hans
Published: February 2011

Reprogramming of gene expression contributes to structural and functional adaptation of muscle tissue in response to altered use. The aim of this study was to investigate mechanisms for observed improvements in leg extension strength, gain in relative thigh muscle mass and loss of body and thigh fat content in response to eccentric and conventional strength training in elderly men (n = 14) and women (n = 14; average age of the men and women: 80.1 ± 3.7 years) by means of structural and molecular analyses. Biopsies were collected from m. vastus lateralis in the resting state before and after 12 weeks of training with two weekly resistance exercise sessions (RET) or eccentric ergometer sessions (EET). Gene expression was analyzed using custom-designed low-density PCR arrays. Muscle ultrastructure was evaluated using EM morphometry. Gain in thigh muscle mass was paralleled by an increase in muscle fiber cross-sectional area (hypertrophy) with RET but not with EET, where muscle growth is likely occurring by the addition of sarcomeres in series or by hyperplasia. The expression of transcripts encoding factors involved in muscle growth, repair and remodeling (e.g. IGF-1, HGF, MYOG, MYH3) was increased to a larger extent after EET than RET. MicroRNA 1 expression was decreased independent of the training modality, and was paralleled by an increased expression of IGF-1 representing a potential target. IGF-1 is a potent promoter of muscle growth, and its regulation by microRNA 1 may have contributed to the gain of muscle mass observed in our subjects. EET depressed genes encoding mitochondrial and metabolic transcripts. The changes of several metabolic and mitochondrial transcripts correlated significantly with changes in mitochondrial volume density. Intramyocellular lipid content was decreased after EET concomitantly with total body fat. Changes in intramyocellular lipid content correlated with changes in body fat content with both RET and EET. In the elderly, RET and EET lead to distinct molecular and structural adaptations which might contribute to the observed small quantitative differences in functional tests and body composition parameters. EET seems to be particularly convenient for the elderly with regard to improvements in body composition and strength but at the expense of reducing muscular oxidative capacity.
Dermoscopy of Pigmented Lesions of the Vulva: A Retrospective Morphological Study
Authors: Ferrari Angela , Zalaudek Iris , Argenziano Giuseppe , Buccini Pierluigi , De Simone Paola , Silipo Vitaliano , Eibenschutz Laura , Mariani Giustino , Covello Renato , Sperduti Isabella , Mariani Luciano , Catricalà Caterina
Published: February 2011

Background: The dermoscopic patterns of pigmented skin tumors are influenced by the body site. Objective: To evaluate the clinical and dermoscopic features associated with pigmented vulvar lesions. Methods: Retrospective analysis of clinical and dermoscopic images of vulvar lesions. The χ2 test was used to test the association between clinical data and histopathological diagnosis. Results: A total of 42 (32.8%) melanocytic and 86 (67.2%) nonmelanocytic vulvar lesions were analyzed. Nevi significantly prevailed in younger women compared with melanomas and melanosis and exhibited most commonly a globular/cobblestone (51.3%) and a mixed (21.6%) pattern. Dermoscopically all melanomas showed a multicomponent pattern. Melanotic macules showed clinical overlapping features with melanoma, but their dermoscopic patterns differed significantly from those observed in melanomas. Conclusion: The diagnosis and management of pigmented vulvar lesions should be based on a good clinicodermoscopic correlation. Dermoscopy may be helpful in the differentiation of solitary melanotic macules from early melanoma.
Dexamethasone and Betamethasone for Prenatal Lung Maturation: Differences in Vascular Endothelial Growth Factor Expression and Alveolarization in Rats
Authors: San Feliciano Laura , Remesal Ana , Isidoro-García María , Ludeña Dolores
Published: February 2011

Background: Fetal and postnatal lung development is regulated by glucocorticoids. The use of antenatal corticosteroids is reported to produce effects on vascular endothelial growth factor (VEGF), which plays a crucial role in pulmonary development. Objectives: The purpose of this study was to compare pulmonary VEGF expression in newborn rats that were exposed to antenatal betamethasone versus dexamethasone and to evaluate its impact on the alveolarization period of rats (0–14 days of life). Methods: Betamethasone, dexamethasone or equivalent saline solution (control group) was administered to pregnant rats on 20th and 21st days of gestation. Pulmonary VEGF mRNA, VEGF protein expression, and alveolarization changes were evaluated at birth and at 14 days of life. Results: Betamethasone and dexamethasone were observed to have different actions on VEGF expression with a correlation with alveolarization on both days of study. Antenatal dexamethasone decreased VEGF expression, betamethasone tended to produce the induction of the expression of VEGF, and moreover, betamethasone did not produce a decrease in alveolarization as seen in the animals that received dexamethasone. Conclusions: Our results support the notion that betamethasone could be a better choice than dexamethasone for antenatal lung maturation.
Long-Term Maternal Separation Differentially Alters Serum Corticosterone Levels and Blood Neutrophil Activity in A/J and C57BL/6 Mouse Offspring
Authors: Pinheiro Milena Lobão , Ferraz-de-Paula Viviane , Ribeiro Alison , Sakai Monica , Bernardi Maria Martha , Palermo-Neto João
Published: February 2011

Objectives: In this work, we searched for maternal separation effects on serum corticosterone levels and blood neutrophil activity in adult male A/J and C57BL/6 mouse offspring. Methods: 40 male A/J mice and 40 male C57BL/6 mice were divided within each strain into two groups. Mice in the maternal separation group were separated from their mothers (1 h/day) on postnatal days 0–13. Mice in the control group were left undisturbed. On postnatal day 45, blood was drawn from all mice and used to assess neutrophil activity by flow cytometry and serum corticosterone levels by radioimmunoassay. Results: The results showed that each mouse strain responded differently to maternal separation, but in both cases, serum corticosterone levels were affected. In both strains, adult mice that experienced maternal separation showed lower serum corticosterone levels than control mice. In relation to control mice kept together with their mothers, the levels of serum corticosterone were 72.7 and 36.36% lower in A/J and C57BL/6 mice submitted to maternal separation, respectively. The current findings showed that maternal separation increased neutrophil activity in mice after reaching adulthood. The observed effects, although in the same direction, differed between A/J and C57BL/6 mice. Maternal separation increased both the percentage and intensity of phagocytosis in C57BL/6 mice, but had no effects on A/J mice. Furthermore, maternal separation increased basal and propidium iodide-labeled Staphylococcus aureus-induced oxidative burst in A/J mice but did not affect oxidative burst in C57BL/6 mice. Finally, phorbol myristate acetate-induced oxidative burst increased in both strains. Conclusion: These results indicate that early maternal separation increases innate immunity, most likely by modifying hypothalamus-pituitary-adrenal axis activity. This suggests that maternal separation is a good model for stress which produces long-term neuroimmune changes whatever the animal species and strain used.
Validation of an Endobronchial Ultrasound Simulator: Differentiating Operator Skill Level
Authors: Stather David R. , MacEachern Paul , Rimmer Karen , Hergott Christopher A. , Tremblay Alain
Published: February 2011

Background: Endobronchial ultrasound (EBUS) is a revolutionary diagnostic procedure. There is currently no accepted method of assessing EBUS technical skill or competency. Objectives: This study aimed to validate a computer EBUS simulator in differentiating between operators of varying clinical EBUS experience. Methods: A convenience sample (n = 22) of bronchoscopists was separated into four cohorts based on previous bronchoscopy experience: group A = novice bronchoscopists, no EBUS experience (n = 4), group B = expert bronchoscopists, no EBUS experience (n = 5), group C = basic clinical EBUS training (n = 9), group D = EBUS experts (n = 4). After a standardized introduction session on the EBUS simulator, participants performed 2 simulated cases on an EBUS simulator with performance metrics measured by the simulator. Results: Significant differences between groups were noted for total procedure time, percentage of lymph nodes identified and percentage of successful biopsies (p < 0.05, ANOVA). Group D performed significantly better than all other groups for total procedure time and percentage of lymph nodes identified (p < 0.05). Group C performed significantly better than groups A and B for total procedure time, percentage of lymph nodes identified and percentage of successful biopsies (p < 0.05, ANOVA). Conclusions: An EBUS simulator can accurately discriminate between operators with different levels of clinical EBUS experience. EBUS simulators show promise as a tool for assessing training and evaluating competency.
The Effect of Tidal Volume on Systemic Inflammation in Acid-Induced Lung Injury
Authors: Walker Melissa G. , Yao Li-Juan , Patterson Eric K. , Joseph Mariamma G. , Cepinskas Gediminas , Veldhuizen Ruud A.W. , Lewis James F. , Yamashita Cory M.
Published: February 2011

Background: Overwhelming systemic inflammation has been implicated in the progression of acute lung injury (ALI) leading to multiple organ failure (MOF) and death. Previous studies suggest that mechanical ventilation (MV) may be a key mediator of MOF through an upregulation of the systemic inflammatory response. Objectives: It was the aim of this study to investigate mechanisms whereby mechanical stress induced by different tidal volumes may contribute to the development of systemic inflammation and maladaptive peripheral organ responses in the setting of ALI. Methods: An acid aspiration model of ALI was employed in 129X1/SVJ mice through an intratracheal administration of hydrochloric acid followed by MV employing either a low (5 ml/kg) or high (12.5 ml/kg) tidal volume ventilation for 120 min. The isolated perfused mouse lung setup was used to assess the specific contribution of the lung to systemic inflammation during MV. Furthermore, lung perfusate collected over the course of MV was used to assess the effects of lung-derived mediators on activation (expression of a proadhesive phenotype) of liver endothelial cells. Results: High tidal volume MV of acid-injured lungs resulted in greater physiologic and histological indices of lung injury compared to control groups. Additionally, there was an immediate and significant release of multiple inflammatory mediators from the lung into the systemic circulation which resulted in greater levels of mRNA adhesion molecule expression in liver endothelial cells in vitro. Conclusions: This study suggests that MV, specifically tidal volume strategy, influences the development of MOF through an upregulation of lung-derived systemic inflammation resulting in maladaptive cellular changes in peripheral organs.
Additional Ablation of Complex Fractionated Atrial Electrograms After Pulmonary Vein Isolation in Patients With Atrial Fibrillation
Authors: Li Wei-ju , Bai Yong-yi , Zhang Hong-yin , Tang Ri-bo , Miao Cheng-long , Sang Cai-hua , Yin Xian-dong , Dong Jian-zeng , Ma Chang-sheng
Published: February 2011

Background—

The efficacy of additional complex fractionated atrial electrogram (CFAE) ablation after pulmonary vein antrum isolation (PVAI) in patients with atrial fibrillation (AF) remains controversial. This meta-analysis was performed to assess the additional efficacy of CFAEs ablation after a single procedure without antiarrhythmic drugs.

Methods and Results—

Trials were identified in MEDLINE, Cochrane Library, Embase, Google Scholar, reviews, and reference lists of relevant papers. Controlled cohort studies comparing the long-term efficacy of combined CFAEs plus PVAI ablation with PVAI alone were included. The primary end point was the maintenance of sinus rhythm without antiarrhythmic drugs. Seven controlled trials (9 comparisons) with a total of 622 participants (332 patients underwent PVAI plus CFAE ablation and 330 patients underwent PVAI alone) were included in the meta-analysis. In an overall pooled estimate, compared with PVI alone, long-term rates of sinus rhythm maintenance (relative risk, 1.17, 95% confidence interval, 1.03 to 1.33,
P
=0.019) were increased by additional CFAE ablation. Subgroup analysis demonstrated that additional CFAEs ablation increased rates of sinus rhythm maintenance in nonparoxysmal AF (relative risk, 1.35; 95% confidence interval, 1.04 to 1.75;
P
=0.022), whereas had no effect on patients with paroxysmal AF (relative risk, 1.04; 95% confidence interval, 0.92 to 1.18;
P
=0.528).

Conclusions—

Adjuvant CFAE ablation in addition to standard PVAI increases the rate of long-term sinus rhythm maintenance in nonparoxysmal AF patients after a single procedure without antiarrhythmic drugs but does not provide additional benefit to sinus rhythm maintenance in paroxysmal AF patients.
Dense Genotyping of Candidate Gene Loci Identifies Variants Associated With High-Density Lipoprotein Cholesterol
Authors: Edmondson Andrew C. , Braund Peter S. , Stylianou Ioannis M. , Khera Amit V. , Nelson Christopher P. , Wolfe Megan L. , DerOhannessian Stephanie L. , Keating Brendan J. , Qu Liming , He Jing , Tobin Martin D. , Tomaszewski Maciej , Baumert Jens , Klopp Norman , Döring Angela , Thorand Barbara , Li Mingyao , Reilly Muredach P. , Koenig Wolfgang , Samani Nilesh J. , Rader Daniel J.
Published: February 2011

Background—

Plasma levels of high-density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs.

Methods and Results—

Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in 3 additional populations for a total meta-analysis in 7857 individuals. We replicated the majority of loci identified through genome-wide association studies and present on the array (including
ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF-PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664
) and provide evidence that suggests an association in several previously unreported candidate gene loci (including
ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4
). There was evidence for multiple, independent association signals in 5 loci, including association with low-frequency nonsynonymous variants.

Conclusions—

Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts comprising subjects at the extremes of the HDL-C distribution may be efficiently used in a case-control discovery of quantitative traits.