bluuebunny/crossref_metadata_2025 huggingface dataset:
Cisplatin Selects for Multidrug-Resistant CD133+ Cells in Lung Adenocarcinoma by Activating Notch Signaling
Authors: Liu Yu-Peng , Yang Chih-Jen , Huang Ming-Shyan , Yeh Chi-Tai , Wu Alexander T.H. , Lee Yu-Cheng , Lai Tsung-Ching , Lee Chien-Hsin , Hsiao Ya-Wen , Lu Jean , Shen Chia-Ning , Lu Pei-Jung , Hsiao Michael
Published: November 2012

Platinum-based chemotherapy is the first-line treatment for non–small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133+ cells are the cause of drug resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133+ cells has not been investigated methodically. In this study, we revealed that CD133+ lung cancer cells labeled by a human CD133 promoter–driven GFP reporter exhibited drug resistance and stem cell characteristics. Treatment of H460 and H661 cell lines with low-dose cisplatin (IC20) was sufficient to enrich CD133+ cells, to induce DNA damage responses, and to upregulate ABCG2 and ABCB1 expression, which therefore increased the cross-resistance to doxorubicin and paclitaxel. This cisplatin-induced enrichment of CD133+ cells was mediated through Notch signaling as judged by increased levels of cleaved Notch1 (NICD1). Pretreatment with the γ-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT), or Notch1 short hairpin RNAs (shRNA) remarkably reduced the cisplatin-induced enrichment of CD133+ cells and increased the sensitivity to doxorubicin and paclitaxel. Ectopic expression of NICD1 reversed the action of DAPT on drug sensitivity. Immunohistochemistry showed that CD133+ cells were significantly increased in the relapsed tumors in three of six patients with lung cancer who have received cisplatin treatment. A similar effect was observed in animal experiments as cisplatin treatment increased Notch1 cleavage and the ratio of CD133+ cells in engrafted tumors. Intratumoral injection of DAPT with cisplatin treatment significantly reduced CD133+ cell number. Together, our results showed that cisplatin induces the enrichment of CD133+ cells, leading to multidrug resistance by the activation of Notch signaling. Cancer Res; 73(1); 406–16. ©2012 AACR.
Combination Therapy Targeting the Chk1 and Wee1 Kinases Shows Therapeutic Efficacy in Neuroblastoma
Authors: Russell Mike R. , Levin Kirill , Rader JulieAnn , Belcastro Lili , Li Yimei , Martinez Daniel , Pawel Bruce , Shumway Stuart D. , Maris John M. , Cole Kristina A.
Published: November 2012

Neuroblastoma is uniquely sensitive to single-agent inhibition of the DNA damage checkpoint kinase Chk1, leading us to examine downstream effectors of this pathway and identify mitotic regulator Wee1 as an additional therapeutic target in this disease. Wee1 was overexpressed in both neuroblastoma cell lines and high-risk patient tumors. Genetic or pharmacologic abrogation of Wee1 signaling results in marked cytotoxicity in 10 of 11 neuroblastoma cell lines with a median IC50 of 300 nmol/L for the Wee1-selective small-molecule inhibitor MK-1775. Murine tumor lines derived from mice that were either heterozygous or homozygous for MycN were particularly sensitive to single-agent inhibition of Wee1 (IC50s of 160 and 62 nmol/L, respectively). Simultaneous pharmacologic inhibition of Chk1 and Wee1 acted in a synergistic fashion to further impede neuroblastoma cell growth in vitro, in a manner greater than the individual inhibitors either alone or combined with chemotherapy. Combination Chk1 and Wee1 inhibition also revealed in vivo efficacy in neuroblastoma xenografts. Taken together, our results show that neuroblastoma cells depend on Wee1 activity for growth and that inhibition of this kinase may serve as a therapeutic for patients with neuroblastoma. Cancer Res; 73(2); 776–84. ©2012 AACR.
A Multicenter, Phase I, Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of Etirinotecan Pegol in Patients with Refractory Solid Tumors
Authors: Jameson Gayle S. , Hamm John T. , Weiss Glen J. , Alemany Carlos , Anthony Stephen , Basche Michele , Ramanathan Ramesh K. , Borad Mitesh J. , Tibes Raoul , Cohn Allen , Hinshaw Ioana , Jotte Robert , Rosen Lee S. , Hoch Ute , Eldon Michael A. , Medve Robert , Schroeder Katrina , White Erica , Von Hoff Daniel D.
Published: November 2012

Purpose: This study was designed to establish the maximum tolerated dose (MTD) and to evaluate tolerability, pharmacokinetics, and antitumor activity of etirinotecan pegol.

Experimental Design: Patients with refractory solid malignancies were enrolled and assigned to escalating-dose cohorts. Patients received 1 infusion of etirinotecan pegol weekly 3 times every 4 weeks (w × 3q4w), or every 14 days (q14d), or every 21 days (q21d), with MTD as the primary end point using a standard 3 + 3 design.

Results: Seventy-six patients were entered onto 3 dosing schedules (58–245 mg/m2). The MTD was 115 mg/m2 for the w × 3q4w schedule and 145 mg/m2 for both the q14d and q21d schedules. Most adverse events related to study drug were gastrointestinal disorders and were more frequent at higher doses of etirinotecan pegol. Late onset diarrhea was observed in some patients, the frequency of which generally correlated with dose density. Cholinergic diarrhea commonly seen with irinotecan treatment did not occur in patients treated with etirinotecan pegol. Etirinotecan pegol administration resulted in sustained and controlled systemic exposure to SN-38, which had a mean half-life of approximately 50 days. Overall, the pharmacokinetics of etirinotecan pegol are predictable and do not require complex dosing adjustments. Confirmed partial responses were observed in 8 patients with breast, colon, lung (small and squamous cell), bladder, cervical, and neuroendocrine cancer.

Conclusion: Etirinotecan pegol showed substantial antitumor activity in patients with various solid tumors and a somewhat different safety profile compared with the irinotecan historical profile. The MTD recommended for phase II clinical trials is 145 mg/m2 q14d or q21d. Clin Cancer Res; 19(1); 268–78. ©2012 AACR.
The Critical Role of Dysregulated FOXM1–PLAUR Signaling in Human Colon Cancer Progression and Metastasis
Authors: Li Dawei , Wei Ping , Peng Zhihai , Huang Chen , Tang Huamei , Jia Zhiliang , Cui Jiujie , Le Xiangdong , Huang Suyun , Xie Keping
Published: November 2012

Purpose: The mammalian Forkhead Box (Fox) transcription factor FOXM1 is implicated in tumorigenesis including mouse intestinal cancer. However, the clinical significance of FOXM1 signaling in human colorectal cancer pathogenesis remains unknown.

Experimental Design: We investigated FOXM1 expression in 203 cases of primary colon cancer and matched normal colon tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on colon cancer growth and metastasis using in vitro and animal models of colon cancer.

Results: We found weak expression of FOXM1 protein in the colon mucosa, whereas we observed strong FOXM1 expression in tumor-cell nuclei of colon cancer and lymph node metastases. A Cox proportional hazards model revealed that FOXM1 expression was an independent prognostic factor in multivariate analysis. Experimentally, overexpression of FOXM1 by gene transfer significantly promoted the growth and metastasis of colon cancer cells in orthotopic mouse models, whereas knockdown of FOXM1 expression by siRNA did the opposite. Promotion of colon tumorigenesis by FOXM1 directly and significantly correlated with activation of urokinase-type plasminogen activator receptor (PLAUR) expression and elevation of invasion and metastasis.

Conclusions: Given the importance of FOXM1 in regulation of the expression of genes key to cancer biology, dysregulated expression and activation of FOXM1 may play important roles in colon cancer progression and metastasis. Clin Cancer Res; 19(1); 62–72. ©2012 AACR.
Phosphoinositide 3-Kinase (PI3K) Pathway Alterations Are Associated with Histologic Subtypes and Are Predictive of Sensitivity to PI3K Inhibitors in Lung Cancer Preclinical Models
Authors: Spoerke Jill M. , O'Brien Carol , Huw Ling , Koeppen Hartmut , Fridlyand Jane , Brachmann Rainer K. , Haverty Peter M. , Pandita Ajay , Mohan Sankar , Sampath Deepak , Friedman Lori S. , Ross Leanne , Hampton Garret M. , Amler Lukas C. , Shames David S. , Lackner Mark R.
Published: November 2012

Purpose: Class 1 phosphatidylinositol 3-kinase (PI3K) plays a major role in cell proliferation and survival in a wide variety of human cancers. Here, we investigated biomarker strategies for PI3K pathway inhibitors in non–small-cell lung cancer (NSCLC).

Experimental Design: Molecular profiling for candidate PI3K predictive biomarkers was conducted on a collection of NSCLC tumor samples. Assays included comparative genomic hybridization, reverse-transcription polymerase chain reaction gene expression, mutation detection for PIK3CA and other oncogenes, PTEN immunohistochemistry, and FISH for PIK3CA copy number. In addition, a panel of NSCLC cell lines characterized for alterations in the PI3K pathway was screened with PI3K and dual PI3K/mTOR inhibitors to assess the preclinical predictive value of candidate biomarkers.

Results: PIK3CA amplification was detected in 37% of squamous tumors and 5% of adenocarcinomas, whereas PIK3CA mutations were found in 9% of squamous and 0% of adenocarcinomas. Total loss of PTEN immunostaining was found in 21% of squamous tumors and 4% of adenocarcinomas. Cell lines harboring pathway alterations (receptor tyrosine kinase activation, PI3K mutation or amplification, and PTEN loss) were exquisitely sensitive to the PI3K inhibitor GDC-0941. A dual PI3K/mTOR inhibitor had broader activity across the cell line panel and in tumor xenografts. The combination of GDC-0941 with paclitaxel, erlotinib, or a mitogen-activated protein–extracellular signal-regulated kinase inhibitor had greater effects on cell viability than PI3K inhibition alone.

Conclusions: Candidate biomarkers for PI3K inhibitors have predictive value in preclinical models and show histology-specific alterations in primary tumors, suggesting that distinct biomarker strategies may be required in squamous compared with nonsquamous NSCLC patient populations. Clin Cancer Res; 18(24); 6771–83. ©2012 AACR.
Clinical and Genetic Characterization of Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Caused by a Plakophilin-2 Splice Mutation
Authors: van der Smagt Jasper J. , van der Zwaag Paul A. , van Tintelen J. Peter , Cox Moniek G.P.J. , Wilde Arthur A.M. , van Langen Irene M. , Ummels Amber , Hennekam F.A.M. , Dooijes Dennis , Gerbens Frans , Bikker Hennie , Hauer Richard N.W. , Doevendans Pieter A.
Published: November 2012

Objectives: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by fibrofatty replacement of cardiomyocytes. In around 50% of index patients, a genetic predisposition is demonstrated. The purpose of this study was to examine a plakophilin-2 (PKP2) splice site mutation, c.2489+4A>C, identified in 4 separately ascertained Dutch ARVD/C families. Methods: Genealogical studies and comprehensive screening of 5 desmosomal genes were undertaken. Reverse transcriptase PCR (RT-PCR) and subsequent sequencing was performed. Results: An A-to-C change (c.2489+4A>C) near the splice donor site of intervening sequence 12 of PKP2 was found in all 4 families. Based on pedigree data and haplotype sharing, a common ancestor should be situated more than 7 generations ago. RT-PCR demonstrated the presence of aberrant messenger RNA. Clinical manifestations ranged from severe disease to nonpenetrance in elderly mutation carriers. Conclusions: This founder mutation in PKP2 is predicted to lead to the presence of a dysfunctional PKP2 protein, whereas most truncating mutations are expected to lead to loss of protein. Mutation carriers displayed a wide range of disease severity, suggesting that PKP2 mutations alone are not sufficient to cause disease, which results in the variable expression and incomplete penetrance characteristic of ARVD/C mutations.
Dutch Translation of the ICMART-WHO Revised Glossary on ART Terminology
Authors: De Neubourg D. , van Duijnhoven N.T.L. , Nelen W.L.D.M. , D’Hooghe T.M.
Published: November 2012

Background: A standardized set of definitions was needed in the field of medically assisted reproduction (MAR) to standardize and harmonize international data acquisition and to monitor the availability, efficacy, and safety of assisted reproductive technology (ART) worldwide. In order to provide accurate national data, the use of a terminology list which was composed and negotiated by the International Committee for Monitoring Assisted Reproductive Technology (ICMART) is essential, and a translation into Dutch was crucial for its implementation in Belgium and the Netherlands. Method: The authors of the Dutch article translated the English publication that appeared simultaneously in Human Reproduction and Fertility and Sterility in 2009. A consensus text was obtained after evaluation by experts in the field of MAR both in the Netherlands and in Belgium and then by the board of the respective organizations of obstetrics and gynecology. It was then sent to the World Health Organization (WHO) for approval of publication. Result: A translation into Dutch of the ICMART terminology of 2009 was obtained after consensus was reached on clinical and laboratory procedures, outcome variables, and birth. Conclusion: The availability and use of standardized terminology and its translation into Dutch will add to a more standardized communication between professionals responsible for the practice of ART and for those responsible for national, regional, and international registries.
Prospective Analysis of Falls in Dominant Ataxias
Authors: Fonteyn E.M.R. , Schmitz-Hübsch T. , Verstappen C.C.P. , Baliko L. , Bloem B.R. , Boesch S. , Bunn L. , Giunti P. , Globas C. , Klockgether T. , Melegh B. , Pandolfo M. , Schöls L. , Timmann D. , van de Warrenburg B.P.C.
Published: November 2012

In a previous retrospective study, we demonstrated that falls are common and often injurious in dominant spinocerebellar ataxias (SCAs) and that nonataxia features play an important role in these falls. Retrospective surveys are plagued by recall bias for the presence and details of prior falls. We therefore sought to corroborate and extend these retrospective findings by means of a prospective extension of this fall study. 113 patients with SCA1, SCA2, SCA3 or SCA6, recruited from the EuroSCA natural history study, were asked to keep a fall diary in between their annual visits to the participating centres. Additionally, patients completed a detailed questionnaire about the first three falls, to identify specific fall circumstances. Relevant disease characteristics were retrieved from the EuroSCA registry. 84.1% of patients reported at least one fall during a time period of 12 months. Fall-related injuries were common and their frequency increased with that of falls. The presence of nonataxia symptoms was associated with a higher fall frequency. This study confirms that falls are a frequent and serious complication of SCA, and that the presence of nonataxia symptoms is an important etiological factor in its occurrence.
Historical Walk: The HRP Special Programme and Infertility
Authors: van der Poel Sheryl Ziemin
Published: November 2012

Background/Aims: The HRP Special Programme (HRP) began addressing ‘reproduction’ problems (infertility) at the same time as ‘fertility regulation’ (contraception). Methods: This report is based upon data collected from official HRP Scientific and Technical Reports. Results: In the 1970s, HRP supported research on human and nonhuman primate models to address the basic biology of reproduction. Importantly, however, it was the multicountry clinical research studies sponsored by HRP during the 1970s and 1980s which led to the identification of not only the large burden of disease but also global patterns of causation of infertility. The next decade saw the development of WHO guidelines and manuals for diagnosis, management, and treatment of infertile women and men, with HRP-sponsored operations research focused on adaptation within primary health care settings. Consensus consultations held during 2001 through 2011 resulted in recommendations to stakeholders, as well as the identification of barriers and inequities in access to infertility care services. Conclusion: With renewed focus on infertility through the current development of revised guidelines and manuals, and the desire to support critical clinical research protocols, including adaptation and implementation research for management and monitoring tools being developed through international partners, HRP will continue to support future success stories in family, maternal, child, and reproductive health.
Clinical Features, Surgical Treatment and Long-Term Outcome in Adult Patients with Moyamoya Disease in China
Authors: Bao Xiang-Yang , Duan Lian , Li De-Sheng , Yang Wei-Zhong , Sun Wei-Jian , Zhang Zheng-Shan , Zong Rui , Han Cong
Published: November 2012

Background: Moyamoya disease (MMD) develops mostly in Asian countries including Japan, Korea, mainland China and Taiwan. However, there are few detailed demographic and clinical data about Chinese patients with MMD. Currently, the most effective treatment in adult patients with MMD is unknown. There have only been a few small case series reporting on encephaloduroarteriosynangiosis (EDAS) in an adult population. Here we describe the clinical features, surgical treatment and long-term outcome of adults with MMD treated at a single institution in China. Methods: Our cohort included 470 adult patients with MMD. The demographic and clinical characteristics were obtained by retrospective chart review and long-term outcome was evaluated using the stroke status. The modified Rankin Scale (mRS) was used to determine the neurological functional outcome. Univariate and multivariate logistic regression analyses were performed to determine risk factors for postoperative morbidity and functional outcome. The risk of subsequent stroke was determined using the Kaplan-Meier method and Cox regression was used to determine risk factors for postoperative or subsequent strokes. Results: The median age for the onset of symptoms was 36.8 (range, 18–59) years. The ratio of female to male patients was 1:1 (231/239). Familial occurrence of MMD was 2.3%. The most common initial symptom was a cerebral ischemic event. The incidence of postoperative ischemic events or hemorrhage was 5.9% (9.8% of patients). Older age at symptom onset, posterior cerebral artery (PCA) involvement and the presence of transient ischemic attack (TIA) were identified as predictors of adverse postoperative events. The Kaplan-Meier estimate stroke risk was 10.1% in the first 2 years, and the 5-year Kaplan-Meier risk of stroke was 13% after surgery for all patients treated with surgical revascularization. Older age at symptom onset, PCA involvement and the presence of TIA were identified as predictors of postoperative or subsequent strokes. Overall, 73.2% of patients had an independent life with no significant disability, with the strongest predictor being the preoperative mRS score. Conclusion: Clinical characteristics of adult MMD in China are different from those in other Asian countries. EDAS in adult patients with MMD carries a low risk, is effective at preventing future ischemic events and improves quality of life.
Learning Curve for Bipolar Transurethral Enucleation and Resection of the Prostate in Saline for Symptomatic Benign Prostatic Hyperplasia: Experience in the First 100 Consecutive Patients
Authors: Xiong Wei , Sun Minghan , Ran Qing , Chen Fang , Du Yangchun , Dou Ke
Published: November 2012

Background: Bipolar transurethral enucleation and resection of the prostate in saline has recently been considered as a safe and technically feasible endoscopic procedure for symptomatic benign prostatic hyperplasia. However, it has not been accepted widely because of the perception of technical difficulty. Methods: A retrospective data review was performed of the first consecutive 100 patients who had undergone bipolar transurethral enucleation and resection of prostatic adenoma. Operative outcome, complications, ratio of conversion to conventional transurethral resection of the prostate and efficiency of tissue enucleation and resection were used to assess the learning curve. Results: Bipolar transurethral enucleation and resection of the prostate was successfully performed in 83 patients. The mean operative time was 117.5 min, and the mean indwelling catheterization was 3.3 ± 1.9 days. After 6 months, maximum urinary flow was 21.34 ± 4.09 ml/s, IPSS was 9.66 ± 2.64, and quality of life was 2.31 ± 0.92 with a residual prostate volume of 35.29 ± 17.57 ml. Regarding the learning curve, the ratio of conversion to conventional bipolar transurethral resection of the prostate decreased after 30 cases, and the efficiency of enucleation and resection increased significantly with accumulative experience after 50 cases. Conclusions: The current results established that bipolar transurethral enucleation and resection of the prostate in saline is a safe and reproducible procedure.
Gonadotropin-Releasing Hormone Analogues Reduce the Proliferation of Endometrial Stromal Cells but Not Endometriotic Cells
Authors: Taniguchi Fuminori , Higaki Hiroko , Azuma Yukihiro , Deura Imari , Iwabe Tomio , Harada Tasuku , Terakawa Naoki
Published: November 2012

Aims: We investigated the potential of gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists to inhibit cell proliferation in endometriotic and endometrial stromal cells. Methods: Twenty patients with ovarian endometriomas and 18 patients with uterine fibromas were recruited. Endometriotic and endometrial stromal cells were obtained from the ovarian chocolate cyst linings and the eutopic endometria of premenopausal women with uterine fibromas, respectively. Results: GnRH agonist or antagonist treatment attenuated tumor necrosis factor (TNF)-α-induced cell proliferation in the endometrial stromal cells, whereas endometriotic stromal cells did not respond to treatment. The endometriotic stromal cells exhibited a decreased expression of the type I GnRH receptor compared with the endometrial stromal cells. GnRH agonists or antagonists did not repress TNF-α-induced IL-8 production in endometriotic stromal cells. Conclusion: GnRH agonists and antagonists have similar effects in slowing the growth of endometrial stromal cells. Endometriotic stromal cells resist the antiproliferative effect of GnRH agonists and antagonists.
Normal Hearing after Trauma with Completely Ectopic Incus – How Possible?
Authors: Zou Y.H. , Liu H.Z. , Yang S.M.
Published: November 2012

Objectives: To report the rare case of a patient with complete incus dislocation after trauma showing normal hearing. Methodology: Physical examination, audiometry, CT of temporal bone, and detection during operation. Results: The incus had become remotely located in the mastoid cavity, but the patient showed normal hearing because fibrous connections had preserved bony continuity. Conclusion: This case demonstrates that disruption of the ossicular chain does not always require ossicular reconstruction.
Effect of Oral JTT-751 (Ferric Citrate) on Hyperphosphatemia in Hemodialysis Patients: Results of a Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Yokoyama Keitaro , Hirakata Hideki , Akiba Takashi , Sawada Kenichi , Kumagai Yuji
Published: November 2012

Background/Aims: JTT-751 (ferric citrate hydrate) is a novel oral, iron-based phosphate binder being developed for the treatment of hyperphosphatemia among chronic kidney disease patients who are on dialysis. This study investigated the dose-response and safety of JTT-751 among Japanese hemodialysis patients. Methods: This was a multicenter, randomized, placebo-controlled, double-blind, parallel-group, comparative study. A total of 192 subjects with serum phosphorus (P) levels between 6.1 and 10.0 mg/dl were randomized to JTT-751 (1.5, 3 or 6 g/day) or to placebo treatment for 28 days. Changes in serum P level from baseline were examined. Results: In the full analysis set, the mean change in serum P level at week 4 was 0.04, –1.28, –2.16 and –4.10 mg/dl in the placebo, 1.5-grams, 3-grams and 6-grams/day groups, respectively, demonstrating a dose-response relationship up to 6 g/day. Overall, a reduction in serum P levels to ≤5.5 mg/dl was achieved in 2.5, 16.7, 50.0 and 92.6% of subjects, in the placebo, 1.5-grams, 3-grams and 6-grams/day groups, respectively. The most common adverse events (AEs) were gastrointestinal disorders. Most AEs were mild. In 25 patients, treatment was discontinued due to increased transferrin saturation ≥50%; however, this was not considered to be a safety issue. Conclusions: When hemodialysis subjects received JTT-751 at doses between 1.5 and 6 g/day for 28 days, serum P levels were significantly reduced in a dose-dependent manner (p < 0.001). JTT-751 was found to be efficacious and safe, with the majority of subjects in the 6-grams/day group achieving a serum P level of ≤5.5 mg/dl.
Apathy and Prospective Memory in Aging
Authors: Esposito Fabienne , Rochat Lucien , Juillerat Van der Linden Anne-Claude , Van der Linden Martial
Published: November 2012

Background: Apathy is common in aging, but the processes underlying its different components are still unclear. The aim of this study was to examine the relationships between apathy and prospective memory (PM), a process involved in the execution of delayed intentions. Methods: Fifty elderly participants completed a PM task and a working memory task. Close relatives of the participants were given the Apathy Inventory, which assesses three dimensions of apathy (lack of initiative, lack of interest, emotional blunting), and a negative mood scale. Results: Correlation analyses showed strong relationships between PM and lack of initiative and interest. These relations remain significant even after controlling for global cognitive functioning, working memory, processing speed and negative mood. Conclusion: This study sheds new light on the cognitive mechanisms associated with apathy in aging and opens up interesting prospects for psychological intervention.
Adrenal Oncocytic Neoplasm: A Systematic Review
Authors: Mearini Luigi , Del Sordo Rachele , Costantini Elisabetta , Nunzi Elisabetta , Porena Massimo
Published: November 2012

Introduction: Oncocytic neoplasms as tumors arising in the adrenal glands are rare, usually considered as nonfunctional and benign. In the current literature, there are extremely limited reports of adrenal oncocytic neoplasms; as to date, only 147 cases have been described. The rarity of the event prompted this study which reviews and presents the incidence, histology, diagnosis and therapy of adrenal oncocytic neoplasms. Materials and Methods: A review by systematic literature search was done using the MEDLINE®/Cochrane libraries from 1950 to date using the medical subject headings ‘oncocytoma', ‘adrenal gland', ‘adrenal oncocytoma', ‘adrenal oncocytic neoplasm' and ‘adrenal oncocytic carcinoma'. Results: Adrenal oncocytic neoplasm is a rare disease, usually incidentally detected because only 17% are functional adrenal masses. The typical oncocyte displays abundant granular eosinophilic cytoplasm, due to the accumulation of mitochondria. Computed tomography and magnetic resonance imaging are not able to identify or differentiate benign and malignant oncocytic neoplasms. The mainstay of therapy is adrenalectomy, recently performed by laparoscopy. The prognosis is good for benign tumors, while adrenocortical oncocytic carcinoma has a poor survival rate of only 5 years. Conclusions: Adrenal oncocytic neoplasm, a rare and mostly benign tumor, usually presents as an incidental, large adrenal mass; surgery is the mainstay of therapy, by means of laparoscopy which is now the most diffuse approach to adrenalectomy.
Genetic Cre-loxP Assessment of Epicardial Cell Fate Using Wt1-Driven Cre Alleles
Authors: Zhou Bin , Pu William T.
Published: November 2012

Rationale:

Wt1-Cre-based tools are important reagents for studying epicardial cell fate and gene function.

Objective:

To better describe the properties of Wt1-Cre-based tools to enhance their use in Cre-loxP-based experiments.

Methods and Results:

In contrast to recently reported results, we show that constitutive Wt1
GFPCre
in combination with certain Cre-activated reporters can be used to trace (pro) epicardial cell fate. Wt1
CreERT2
can be efficiently induced by tamoxifen administration. We show substantial labeling of coronary endothelial cells when induction is performed at late but not early stages of heart development.

Conclusions:

Wt1-based Cre alleles are useful tools for genetic lineage tracing of epicardial cells and mesothelium of other organs. Using these tools with proper understanding of their properties and limitations enables genetic labeling of epicardial cells and their derivatives.
Randomized Comparison of Sevoflurane Versus Propofol to Reduce Perioperative Myocardial Ischemia in Patients Undergoing Noncardiac Surgery
Authors: Lurati Buse Giovanna A.L. , Schumacher Philippe , Seeberger Esther , Studer Wolfgang , Schuman Regina M. , Fassl Jens , Kasper Jorge , Filipovic Miodrag , Bolliger Daniel , Seeberger Manfred D.
Published: November 2012

Background—

Volatile anesthetics provide myocardial preconditioning in coronary surgery patients. We hypothesized that sevoflurane compared with propofol reduces the incidence of myocardial ischemia in patients undergoing major noncardiac surgery.

Methods and Results—

We enrolled 385 patients at cardiovascular risk in 3 centers. Patients were randomized to maintenance of anesthesia with sevoflurane or propofol. We recorded continuous ECG for 48 hours perioperatively, measured troponin T and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) on postoperative days 1 and 2, and evaluated postoperative delirium by the Confusion Assessment Method. At 6 and 12 months, we contacted patients by telephone to assess major adverse cardiac events. The primary end point was a composite of myocardial ischemia detected by continuous ECG and/or troponin elevation. Additional end points were postoperative NT-proBNP concentrations, major adverse cardiac events, and delirium. Patients and outcome assessors were blinded. We tested dichotomous end points by χ
2
test and NT-proBNP by Mann–Whitney test on an intention-to-treat basis. Myocardial ischemia occurred in 75 patients (40.8%) in the sevoflurane and 81 (40.3%) in the propofol group (relative risk, 1.01; 95% confidence interval, 0.78–1.30). NT-proBNP release did not differ across allocation on postoperative day 1 or 2. Within 12 months, 14 patients (7.6%) suffered a major adverse cardiac event after sevoflurane and 17 (8.5%) after propofol (relative risk, 0.90; 95% confidence interval, 0.44–1.83). The incidence of delirium did not differ (11.4% versus 14.4%;
P
=0.379).

Conclusions—

Compared with propofol, sevoflurane did not reduce the incidence of myocardial ischemia in high-risk patients undergoing major noncardiac surgery. The sevoflurane and propofol groups did not differ in postoperative NT-proBNP release, major adverse cardiac events at 1 year, or delirium.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00286585.
Coronary Artery Bypass Surgery With or Without Mitral Valve Annuloplasty in Moderate Functional Ischemic Mitral Regurgitation
Authors: Chan K.M. John , Punjabi Prakash P. , Flather Marcus , Wage Riccardo , Symmonds Karen , Roussin Isabelle , Rahman-Haley Shelley , Pennell Dudley J. , Kilner Philip J. , Dreyfus Gilles D. , Pepper John R.
Published: November 2012

Background—

The role of mitral valve repair (MVR) during coronary artery bypass grafting (CABG) in patients with moderate ischemic mitral regurgitation (MR) is uncertain. We conducted a randomized, controlled trial to determine whether repairing the mitral valve during CABG may improve functional capacity and left ventricular reverse remodeling compared with CABG alone.

Methods and Results—

Seventy-three patients referred for CABG with moderate ischemic MR and an ejection fraction >30% were randomized to receive CABG plus MVR (34 patients) or CABG only (39 patients). The study was stopped early after review of interim data. At 1 year, there was a greater improvement in the primary end point of peak oxygen consumption in the CABG plus MVR group compared with the CABG group (3.3 mL/kg/min versus 0.8 mL/kg/min;
P
<0.001). There was also a greater improvement in the secondary end points in the CABG plus MVR group compared with the CABG group: left ventricular end-systolic volume index, MR volume, and plasma B-type natriuretic peptide reduction of 22.2 mL/m
2
, 28.2 mL/beat, and 557.4 pg/mL, respectively versus 4.4 mL/m
2
(
P
=0.002), 9.2 mL/beat (
P
=0.001), and 394.7 pg/mL (
P
=0.003), respectively. Operation duration, blood transfusion, intubation duration, and hospital stay duration were greater in the CABG plus MVR group. Deaths at 30 days and 1 year were similar in both groups: 3% and 9%, respectively in the CABG plus MVR group, versus 3% (
P
=1.00) and 5% (
P
=0.66), respectively in the CABG group.

Conclusions—

Adding mitral annuloplasty to CABG in patients with moderate ischemic MR may improve functional capacity, left ventricular reverse remodeling, MR severity, and B-type natriuretic peptide levels, compared with CABG alone. The impact of these benefits on longer term clinical outcomes remains to be defined.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00413998.
On the Taxonomy of Optimization Problems Under Estimation of Distribution Algorithms
Authors: Echegoyen Carlos , Mendiburu Alexander , Santana Roberto , Lozano Jose A.
Published: November 2012

Understanding the relationship between a search algorithm and the space of problems is a fundamental issue in the optimization field. In this paper, we lay the foundations to elaborate taxonomies of problems under estimation of distribution algorithms (EDAs). By using an infinite population model and assuming that the selection operator is based on the rank of the solutions, we group optimization problems according to the behavior of the EDA. Throughout the definition of an equivalence relation between functions it is possible to partition the space of problems in equivalence classes in which the algorithm has the same behavior. We show that only the probabilistic model is able to generate different partitions of the set of possible problems and hence, it predetermines the number of different behaviors that the algorithm can exhibit. As a natural consequence of our definitions, all the objective functions are in the same equivalence class when the algorithm does not impose restrictions to the probabilistic model. The taxonomy of problems, which is also valid for finite populations, is studied in depth for a simple EDA that considers independence among the variables of the problem. We provide the sufficient and necessary condition to decide the equivalence between functions and then we develop the operators to describe and count the members of a class. In addition, we show the intrinsic relation between univariate EDAs and the neighborhood system induced by the Hamming distance by proving that all the functions in the same class have the same number of local optima and that they are in the same ranking positions. Finally, we carry out numerical simulations in order to analyze the different behaviors that the algorithm can exhibit for the functions defined over the search space [Formula: see text].
Models of Performance of Evolutionary Program Induction Algorithms Based on Indicators of Problem Difficulty
Authors: Graff Mario , Poli Riccardo , Flores Juan J.
Published: November 2012

Modeling the behavior of algorithms is the realm of evolutionary algorithm theory. From a practitioner's point of view, theory must provide some guidelines regarding which algorithm/parameters to use in order to solve a particular problem. Unfortunately, most theoretical models of evolutionary algorithms are difficult to apply to realistic situations. However, in recent work (Graff and Poli, 2008 , 2010 ), where we developed a method to practically estimate the performance of evolutionary program-induction algorithms (EPAs), we started addressing this issue. The method was quite general; however, it suffered from some limitations: it required the identification of a set of reference problems, it required hand picking a distance measure in each particular domain, and the resulting models were opaque, typically being linear combinations of 100 features or more. In this paper, we propose a significant improvement of this technique that overcomes the three limitations of our previous method. We achieve this through the use of a novel set of features for assessing problem difficulty for EPAs which are very general, essentially based on the notion of finite difference. To show the capabilities or our technique and to compare it with our previous performance models, we create models for the same two important classes of problems—symbolic regression on rational functions and Boolean function induction—used in our previous work. We model a variety of EPAs. The comparison showed that for the majority of the algorithms and problem classes, the new method produced much simpler and more accurate models than before. To further illustrate the practicality of the technique and its generality (beyond EPAs), we have also used it to predict the performance of both autoregressive models and EPAs on the problem of wind speed forecasting, obtaining simpler and more accurate models that outperform in all cases our previous performance models.
You’re a Mean One, Mr. Gingrich
Authors: Brattebo Douglas M.
Published: November 2012

Newt Gingrich’s unexpected and fleeting political resurgence in late 2011 and early 2012 provides a perfect opportunity to take stock of Gingrich’s role in bringing about the current dysfunction in American politics. This article focuses on five aspects of Gingrich’s approach to politics that have contributed significantly to the ongoing crisis of confidence in U.S. political institutions and the dearth of civility in American political life: (a) treating people as a means to an end, (b) attacking the character of opponents, (c) investigating opponents as a political ploy, (d) holding others to higher standards of behavior, and (e) divorcing the cultivation of extremism to obtain power from the preconditions for governing.
Parallel agent-based simulation with Repast for High Performance Computing
Authors: Collier Nicholson , North Michael
Published: November 2012

In the last decade, agent-based modeling and simulation (ABMS) has been applied to a variety of domains, demonstrating the potential of this technique to advance science, engineering, and policy analysis. However, realizing the full potential of ABMS to find breakthrough research results requires far greater computing capability than is available through current ABMS tools. The Repast for High Performance Computing (Repast HPC) project addresses this need by developing a useful and useable next-generation ABMS system explicitly focusing on larger-scale distributed computing platforms. Repast HPC is intended to smooth the path from small-scale simulations to large-scale distributed simulations through the use of a Logo-like system. This article’s contribution is its detailed presentation of the implementation of Repast HPC as a useful and usable framework, a complete ABMS platform developed explicitly for larger-scale distributed computing systems that leverages modern C + + techniques and the ReLogo language.
An investigation into the performance of a new mechanical thrombectomy device using bond graph modeling: application to the extraction of blood clots in the middle cerebral artery
Authors: Romero Gregorio , Martinez M Luisa , Pearce Gillian , Mera J Manuel
Published: November 2012

A number of thrombectomy devices using a variety of methods have now been developed to facilitate clot removal. We present research involving one such experimental device recently developed in the UK, called a ‘GP’ Thrombus Aspiration Device (GPTAD). This device has the potential to bring about the extraction of a thrombus. Although the device is at a relatively early stage of development, the results look encouraging. In this work, we present an analysis and modeling of the GPTAD by means of the bond graph technique; it seems to be a highly effective method of simulating the device under a variety of conditions. Such modeling is useful in optimizing the GPTAD and predicting the result of clot extraction. The aim of this simulation model is to obtain the minimum pressure necessary to extract the clot and to verify that both the pressure and the time required to complete the clot extraction are realistic for use in clinical situations, and are consistent with any experimentally obtained data. We therefore consider aspects of rheology and mechanics in our modeling.
Subdue the Senate
Authors: McCormick John P.
Published: November 2012

This article analyzes Machiavelli’s accounts of the historical figures Agathocles, Clearchus, Appius and Pacuvius to (1) accentuate the Florentine’s distinction between tyranny and civic leadership, (2) identify the proper place of elite punishment and popular empowerment in his conception of democratic politics, and (3) criticize contemporary Straussian and “radical” interpreters of Machiavelli for profoundly underestimating the roles that popular judgment and popular rule play within his political thought.
Plebeian Politics
Authors: Winter Yves
Published: November 2012

In his Florentine Histories, Machiavelli offers an ambivalent portrayal of the revolt of the textile workers in late fourteenth-century Florence, known as the tumult of the Ciompi. On the face of it, Machiavelli’s depiction of the insurgent workers is not exactly flattering. Yet this picture is undermined by a firebrand speech, which Machiavelli invents and attributes to an unnamed leader of the plebeian revolt. I interpret this speech as a radical and egalitarian vector of thought opened up by Machiavelli’s text. The revolutionary address reveals an untimely and not entirely self-conscious political radicalism, a plebeian politics that repudiates the logic of oligarchic privilege and is simultaneously not available for subsumption under the mantle of civic republicanism.
Everything and nothing changes: Fast-food employers and the threat to minimum wage regulation in Ireland
Authors: O’Sullivan Michelle , Royle Tony
Published: November 2012

Ireland’s selective system of collective agreed minimum wages has come under significant pressure in recent years. A new fast-food employer body took a constitutional challenge against the system of Joint Labour Committees (JLCs) and this was strengthened by the discourse on the negative effects of minimum wages as Ireland’s economic crisis worsened. Taking a historical institutional approach, the article examines the critical juncture for the JLC system and the factors which led to the subsequent government decision to retain but reform the system. The article argues that the improved enforcement of minimum wages was a key factor in the employers’ push for abolition of the system but that the legacy of a collapsed social partnership system prevented the system’s abolition.
The foundations of social cognition: Studies on face/voice integration in newborn infants
Authors: Streri Arlette , Coulon Marion , Guellaï Bahia
Published: November 2012

A series of studies on newborns’ abilities for recognizing speaking faces has been performed in order to identify the fundamental cues of social cognition. We used audiovisual dynamic faces rather than photographs or patterns of faces. Direct eye gaze and speech addressed to newborns, in interactive situations, appear to be two good candidates for this function. Both enable a correct identification and recognition of an unfamiliar person by the infants. Moreover, a few hours after birth, newborns are also capable of imitating a model (Mouth Opening or Lip Spreading) more quickly if it is associated with the pronunciation of a vowel, /a/ or /i/. Newborns are very sensitive to natural speech compared to filtered speech. These findings reveal the existence of an innate predisposition to social interactions in newborns.
Oxygen treatment is effective in migraine with autonomic symptoms
Authors: Jürgens Tim P , Schulte Laura H , May Arne
Published: November 2012

Introduction

While inhalation of high-flow 100% oxygen is highly effective in cluster headache, studies on its efficacy in migraine are sparse and controversial.

Case

We report the case of a 22-year-old patient with an eight-year history of strictly unilateral migraine without aura but cranial autonomic symptoms. She repeatedly responded completely to inhalation of high-flow pure oxygen within 15 min but suffered from recurrence of attacks within 30 min after discontinuation.

Discussion

In line with experimental animal studies, this case suggests a clinically relevant efficacy of inhaled oxygen in patients with migraine with accompanying cranial autonomic symptoms.
Microfracture for Acetabular Chondral Defects in Patients With Femoroacetabular Impingement
Authors: Karthikeyan Shanmugam , Roberts Sally , Griffin Damian
Published: November 2012

Background:

Microfracture is a proven technique to treat articular cartilage defects in the knee. However, there is little evidence in the literature to confirm the ability of microfracture to produce repair tissue in the hip joint.

Purpose:

The purpose of this study was to report the macroscopic and microscopic appearances of repair tissue after microfracture performed at hip arthroscopic surgery for isolated full-thickness acetabular cartilage defects in patients with femoroacetabular impingement (FAI).

Study Design:

Case series; Level of evidence, 4.

Methods:

Twenty patients who underwent arthroscopic surgery for FAI had a localized full-thickness acetabular chondral defect treated by microfracture and then underwent a later second-look hip arthroscopic procedure. The size of the full-thickness defect was measured at the primary arthroscopic procedure. A visual assessment of the extent and quality of repair tissue was performed at second-look arthroscopic surgery. Two patients also had a biopsy of the repair tissue, which was studied histologically.

Results:

At an average follow-up of 17 months, 19 of the 20 patients had a mean fill of 96% ± 7% with macroscopically good quality repair tissue. One patient had only a 25% fill with poor quality repair tissue. Histologically, the tissue was found to be primarily fibrocartilage with some staining for type II collagen in the region closest to the bone.

Conclusion:

Microfracture in the hip appears to be an effective technique that produces excellent coverage of the defect with good quality repair tissue on visual inspection and microscopic examination at an average follow-up of 17 months.
Bioactive coatings for coronary stents: Modulation of cell proliferation by controlled release of anti-proliferative drugs
Authors: Rodríguez Gema , Fernández-Gutiérrez Mar , Parra Juan , López-Bravo Antonio , Molina María , Duocastella Luis , San Román Julio
Published: November 2012

Drug eluting coronary stents coated with a bioactive and biostable polymer system (THBA70), based on acrylate copolymers bearing a salicylic acid derivative as side substituent, were evaluated. The microstructural architecture of the copolymer THBA70 comprises a random copolymer of a methacrylate derivative from triflusal (4-trifluoromethyl salicylic acid) with 45 mol% of THEMA (2-methacryloyloxyethyl [2-(acetyloxy)-4-(trifluoromethyl)] benzoate), which makes the system anti-thrombogenic with good adhesion to the surface of metallic stents. The bioactive coating prevented thrombosis, an adverse effect associated with the implantation of drug-eluting stents. The in vitro drug delivery of drug-eluting stents under dynamic conditions indicated excellent controlled drug release. The THBA70 films loaded with relatively low concentrations of taxol or simvastatin in contact with fibroblasts produced inhibition of cell proliferation with a dose-dependent bioactivity.