bluuebunny/crossref_metadata_2025 huggingface dataset:
A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Panobinostat, an HDAC Inhibitor, Combined with Erlotinib in Patients with Advanced Aerodigestive Tract Tumors
Authors: Gray Jhanelle E. , Haura Eric , Chiappori Alberto , Tanvetyanon Tawee , Williams Charles C. , Pinder-Schenck Mary , Kish Julie A. , Kreahling Jenny , Lush Richard , Neuger Anthony , Tetteh Leticia , Akar Angela , Zhao Xiuhua , Schell Michael J. , Bepler Gerold , Altiok Soner
Published: January 2014

Purpose: Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non–small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer.

Experimental Design: Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre and posttherapy tumor biopsies for checkpoint kinase 1 (CHK1) expression were assessed.

Results: Of 42 enrolled patients, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1–3), and rash and anorexia (grades 1–2). Disease control rates were 54% for NSCLC (n = 26) and 43% for head and neck cancer (n = 7). Of 7 patients with NSCLC with EGF receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P = 0.43) and overall survival was 41 (estimated) versus 5.2 months (P = 0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat's pharmacodynamic effect in blood, FPB, and tumor samples. Low CHK1 expression levels correlated with PFS (P = 0.006) and response (P = 0.02).

Conclusions: We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore the benefits of HDAC inhibitors in patients with EGFR-mutant NSCLC, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1's predictive role. Clin Cancer Res; 20(6); 1644–55. ©2014 AACR.
Genetic and Pharmacologic Evidence That mTOR Targeting Outweighs mTORC1 Inhibition as an Antimyeloma Strategy
Authors: Chen Xi , Díaz-Rodríguez Elena , Ocio Enrique M. , Paiva Bruno , Mortensen Deborah S. , Lopez-Girona Antonia , Chopra Rajesh , Miguel Jesús San , Pandiella Atanasio
Published: January 2014

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth, proliferation, metabolism, and cell survival, and plays those roles by forming two functionally distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Deregulation of the mTOR pathway has been found in different cancers, including multiple myeloma. Agents acting on mTORC1, such as rapamycin and derivatives, are being explored as antitumoral strategies. However, whether targeting mTOR would be a more effective antimyeloma strategy than exclusively acting on the mTORC1 branch remains to be established. In this report, we explored the activation status of mTOR routes in malignant plasma cells, and analyzed the contribution of mTOR and its two signaling branches to the proliferation of myeloma cells. Gene expression profiling demonstrated deregulation of mTOR pathway–related genes in myeloma plasma cells from patients. Activation of the mTOR pathway in myelomatous plasma cells was corroborated by flow cytometric analyses. RNA interference (RNAi) experiments indicated that mTORC1 predominated over mTORC2 in the control of myeloma cell proliferation. However, mTOR knockdown had a superior antiproliferative effect than acting only on mTORC1 or mTORC2. Pharmacologic studies corroborated that the neutralization of mTOR has a stronger antimyeloma effect than the individual inhibition of mTORC1 or mTORC2. Together, our data support the clinical development of agents that widely target mTOR, instead of agents, such as rapamycin or its derivatives, that solely act on mTORC1. Mol Cancer Ther; 13(2); 504–16. ©2014 AACR.
Mutant Ras Elevates Dependence on Serum Lipids and Creates a Synthetic Lethality for Rapamycin
Authors: Salloum Darin , Mukhopadhyay Suman , Tung Kaity , Polonetskaya Aleksandra , Foster David A.
Published: January 2014

The conversion of normal cells to cancer cells involves a shift from catabolic to anabolic metabolism involving increased glucose uptake and the diversion of glycolytic intermediates into nucleotides, amino acids, and lipids needed for cell growth. An underappreciated aspect of nutrient uptake is the utilization of serum lipids. We investigated the dependence of human cancer cells on serum lipids and report here that Ras-driven human cancer cells are uniquely dependent on serum lipids for both proliferation and survival. Removal of serum lipids also sensitizes Ras-driven cancer cells to rapamycin—indicating that the enhanced need for serum lipids creates a synthetic lethal phenotype that could be exploited therapeutically. Although depriving humans of serum lipids is not practical, suppressing uptake of lipids is possible. Suppressing macropinocytosis in Ras-driven cancer cells also created sensitivity to suppression of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1). It is speculated that this property displayed by Ras-driven cancer cells represents an Achilles' heel for the large number of human cancers that are driven by activating Ras mutations. Mol Cancer Ther; 13(3); 733–41. ©2014 AACR.
Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution
Authors: Dewhurst Sally M. , McGranahan Nicholas , Burrell Rebecca A. , Rowan Andrew J. , Grönroos Eva , Endesfelder David , Joshi Tejal , Mouradov Dmitri , Gibbs Peter , Ward Robyn L. , Hawkins Nicholas J. , Szallasi Zoltan , Sieber Oliver M. , Swanton Charles
Published: January 2014

The contribution of whole-genome doubling to chromosomal instability (CIN) and tumor evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploid colon cancer progenitor to investigate how a genome-doubling event affects genome stability over time. Rare cells that survive genome doubling demonstrate increased tolerance to chromosome aberrations. Tetraploid cells do not exhibit increased frequencies of structural or numerical CIN per chromosome. However, the tolerant phenotype in tetraploid cells, coupled with a doubling of chromosome aberrations per cell, allows chromosome abnormalities to evolve specifically in tetraploids, recapitulating chromosomal changes in genomically complex colorectal tumors. Finally, a genome-doubling event is independently predictive of poor relapse-free survival in early-stage disease in two independent cohorts in multivariate analyses [discovery data: hazard ratio (HR), 4.70, 95% confidence interval (CI), 1.04–21.37; validation data: HR, 1.59, 95% CI, 1.05–2.42]. These data highlight an important role for the tolerance of genome doubling in driving cancer genome evolution.

Significance: Our work sheds light on the importance of whole-genome–doubling events in colorectal cancer evolution. We show that tetraploid cells undergo rapid genomic changes and recapitulate the genetic alterations seen in chromosomally unstable tumors. Furthermore, we demonstrate that a genome-doubling event is prognostic of poor relapse-free survival in this disease type. Cancer Discov; 4(2); 175–85. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 131
Role of Statin in Atrial Fibrillation-Related Stroke: An Angiographic Study for Collateral Flow
Authors: Lee Mi Ji , Bang Oh Young , Kim Suk Jae , Kim Gyeong Moon , Chung Chin Sang , Lee Kwang Ho , Ovbiagele Bruce , Liebeskind David S. , Saver Jeffrey L. ,   for the UCLA-Samsung Stroke Collaborators
Published: January 2014

Background: Currently, intensive lipid lowering is recommended in patients with atherosclerotic ischemic stroke or transient ischemic attack. However, the role of statin in cardioembolic stroke is unclear. We investigated the association of statin with pretreatment collateral status in cardioembolic stroke. Methods: A collaborative study from two stroke centers in distinct geographic regions included consecutive patients with acute middle cerebral artery (MCA) infarction due to atrial fibrillation (AF) who underwent cerebral angiography. The relationship between pretreatment collateral grade and the use/dose of statin at stroke onset was assessed. The angiographic collateral grade was evaluated according to the ASITN/SIR Collateral Flow Grading System. Results: Ninety-eight patients (76 statin-naïve, 22 statin users) were included. Compared with statin-naïve patients, statin users were older and more frequently had hypertension, hyperlipidemia and coronary heart disease. Excellent collaterals (grade 3-4) were more frequently observed in statin users (11 patients, 50%) than in statin-naïve patients (21 patients, 27.6%; p = 0.049). The use of atorvastatin 10 mg equivalent or higher doses of statin was associated with excellent collaterals (p for trend = 0.025). In multiple regression analysis, prestroke statin use was independently associated with excellent collaterals (odds ratio, 7.841; 95% confidence interval, CI, 1.96-31.363; p = 0.004). Conclusions: Premorbid use of statin in AF patients is associated with excellent collateral flow. Although most statin trials excluded patients with cardioembolic stroke, our data suggests the possibility that statin may be beneficial in AF-related stroke.
A Minimally Invasive Technique for Occluding Large Muscular Ventricular Septal Defects in Infants
Authors: Gao Zibo , Wu Qin , Zhao Tianli , Yin Ni , Gao Lei , Xu Xinhua , Xie Li , Yang Yifeng , Yang Jinfu
Published: January 2014

Objective: This study investigated the feasibility, timing and indications for closure of large muscular ventricular septal defects (VSDs) in infants without use of a cardiopulmonary bypass. Methods: A total of 9 infants with large muscular VSDs ranging in size from 7 to 15 mm were treated by minimally invasive closure without cardiopulmonary bypass between April 2010 and February 2013. Results: All surgeries were successful without resulting in uncontrolled systemic infection, a pulmonary hypertensive crisis or a severely low cardiac output, and with an apparently shorter operation time and postoperative tracheal cannula. Conclusions: VSD closure without cardiopulmonary bypass can improve the efficacy and prognosis of infants with large muscular VSDs and concurrent pulmonary infections or respiratory failure.
Early Detection of Lung Cancer: A Statement from an Expert Panel of the Swiss University Hospitals on Lung Cancer Screening
Authors: Frauenfelder T. , Puhan M.A. , Lazor R. , von Garnier C. , Bremerich J. , Niemann T. , Christe A. , Montet X. , Gautschi O. , Weder W. , Kohler M. ,   on behalf of the expert panel
Published: January 2014

The discussion about setting up a program for lung cancer screening was launched with the publication of the results of the National Lung Screening Trial, which suggested reduced mortality in high-risk subjects undergoing CT screening. However, important questions about the benefit-harm balance and the details of a screening program and its cost-effectiveness remain unanswered. A panel of specialists in chest radiology, respiratory medicine, epidemiology, and thoracic surgery representing all Swiss university hospitals prepared this joint statement following several meetings. The panel argues that premature and uncontrolled introduction of a lung cancer screening program may cause substantial harm that may remain undetected without rigorous quality control. This position paper focuses on the requirements of running such a program with the objective of harmonizing efforts across the involved specialties and institutions and defining quality standards. The underlying statement includes information on current evidence for a reduction in mortality with lung cancer screening and the potential epidemiologic implications of such a program in Switzerland. Furthermore, requirements for lung cancer screening centers are defined, and recommendations for both the CT technique and the algorithm for lung nodule assessment are provided. In addition, related issues such as patient management, registry, and funding are addressed. Based on the current state of the knowledge, the panel concludes that lung cancer screening in Switzerland should be undertaken exclusively within a national observational study in order to provide answers to several critical questions before considering broad population-based screening for lung cancer.
Preparation of Cell Blocks for Lung Cancer Diagnosis and Prediction: Protocol and Experience of a High-Volume Center
Authors: Kossakowski Claudia A. , Morresi-Hauf Alicia , Schnabel Philipp A. , Eberhardt Ralf , Herth Felix J.F. , Warth Arne
Published: January 2014

Minimally invasive diagnostic techniques are increasingly being used to obtain specimens for pathological diagnosis and prediction. Referring to lung cancer, both endobronchial and endoesophageal ultrasound are used worldwide as diagnostic routine methods. Consequently, an increasing number of pathological samples are cytological and fewer are histological. On the other hand, the requirements for specific and sensitive tumor subtyping complemented by predictive analyses are steadily increasing and are an essential basis for evidence-based treatment decisions. In this article we focus on the cell block method as a helpful tool for diagnostic and predictive analyses in lung cancer and point out its advantages and disadvantages in comparison to conventional cytological and biopsy specimens. Furthermore, we retrospectively analyze the diagnostic results of the cell block method in a high-volume center over 5 years. The main advantages of cell blocks are the availability of established and validated protocols, archiving and the opportunity to have serial sections from the same specimens to provide or repeat molecular analyses. Actually, in case of tumor progression, even additional biomarkers can be tested using the original cell block when re-biopsies are not feasible. The cell block method should be considered as a reliable, complimentary approach to conventional cytological or biopsy procedures, which is helpful to fulfill the increasing requirements of high-quality diagnostics and prediction.
Immediate Effects of Unaffected Arm Exercise in Poststroke Patients with Spastic Upper Limb Hemiparesis
Authors: Sakamoto Keiko , Nakamura Takeshi , Uenishi Hiroyasu , Umemoto Yasunori , Arakawa Hideki , Abo Masahiro , Saura Ryuichi , Fujiwara Hiroyoshi , Kubo Toshikazu , Tajima Fumihiro
Published: January 2014

Background: Spasticity is a major disabling symptom in stroke patients. Clinically, one of the goals of management of stroke patients should be to reduce spasticity. Recent evidence suggests that motor recovery after stroke comprises a hierarchical, dynamic framework of interacting mechanisms in brain cortex. We hypothesized that unaffected arm exercise can stimulate the ipsilateral motor cortex and change the affected upper limb function and spasticity in stroke patients. To test the hypothesis, we evaluated the effects of unaffected arm exercise on spasticity of the affected upper limb and motor function in stroke patients. Methods: The study was performed in 41 chronic stroke patients with upper limb hemiparesis. Affected upper limb spasticity and function were assessed at baseline and after each intervention by the modified Ashworth Scale and Fugl-Meyer Assessment, respectively. Patients were also evaluated clinically by the modified Rankin Scale, Functional Independence Measurement and National Institutes of Health Stroke Scale. Subjects stood for 10 min during the control period, and then cycled an arm crank ergometer at 50% of maximum work load for 10 min by the unaffected arm in standing position. Results: The mean age at study entry was 64.6 ± 1.7 years. The latency between onset of stroke and the study was 109.0 ± 17.0 months (range, 6-495). The cause of hemiparesis was cerebral infarction (n = 21), intracerebral hemorrhage (n = 17) or subarachnoid hemorrhage (n = 3). Exercise significantly improved the modified Ashworth Scale compared with baseline (p < 0.0001). No such change was noted after the control intervention. The Fugl-Meyer Assessment score did not change after exercise compared with baseline (p = 0.95). Conclusions: We conclude that 10 min of unaffected arm exercise improves the affected upper limb spasticity in stroke patients. Further studies are needed to determine the exact mechanism of such improvement and the long-term effects of unaffected arm exercise on motor performance.
Rosuvastatin Suppresses the Oxidative Response in the Venous Limb of an Arteriovenous Fistula and Enhances the Fistula Blood Flow in Diabetic Rats
Authors: Fang Shih-Yuan , Roan Jun-Neng , Lin Yu , Hsu Chih-Hsin , Chang Shih-Wei , Huang Chein-Chi , Tsai Yu-Chuan , Lam Chen-Fuh
Published: January 2014

Objective: The blood flow in the arteriovenous (AV) fistula is significantly reduced in diabetic patients. Statins are known to mediate pleiotropic effects in the vascular endothelium and attenuate inflammatory responses. This study tested the vascular protective effect of rosuvastatin in an experimental model of AV fistula. Methods: One week after the induction of diabetes mellitus (DM) in rats, a fistula was created in the abdominal aorta and inferior vena cava. Rats received placebo or rosuvastatin (15 mg/kg/day) in chow for 2 weeks. The blood flow in the venous segments of the fistula was measured. The expression of proinflammatory genes and the generation of superoxide in the venous fistula were examined. Results: The blood flow and luminal diameter of the AV fistula was significantly enhanced in animals treated with rosuvastatin. Rosuvastatin attenuated the expression of inducible nitric oxide synthase, NADPH oxidase, and monocyte chemotactic protein-1 in the fistula. The levels of superoxide anions and proinflammatory cytokines were also suppressed in rosuvastatin-treated animals. Neointimal formation in the AV fistula was not affected following treatment with rosuvastatin. Conclusions: We demonstrated that rosuvastatin improves luminal dilatation and blood flow in the AV fistula of subjects with DM. These vascular protective effects of rosuvastatin are most likely mediated by the attenuation of proinflammatory activities in the remodeled vasculature.
Chymase Inhibition Attenuates Lipopolysaccharide/ D-Galactosamine-Induced Acute Liver Failure in Hamsters
Authors: Imai Yoshiro , Takai Shinji , Jin Denan , Komeda Koji , Tashiro Keitaro , Li Zhong-Lian , Otsuki Yoshinori , Okamura Haruki , Hayashi Michihiro , Uchiyama Kazuhisa
Published: January 2014

Background/Aims: Chymase inhibition has been shown to attenuate matrix metalloproteinase (MMP)-9 and tumor necrosis factor (TNF)-α, both of which are associated with the pathogenesis of acute liver failure (ALF). This study investigated the effects of the chymase inhibitor TY-51469 on lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced ALF in hamsters. Methods: TY-51469 (10 or 30 mg/kg) or placebo was administered 1 h before the LPS (160 µg/kg)/GalN (400 mg/kg) injection. Results: Hepatic chymase activity was significantly increased after the LPS/GalN injection, but the significant increase was dose-dependently and significantly attenuated by treatment with TY-51469. Significant increases in hepatic MMP-9 activity and TNF-α concentration were observed after the LPS/GalN injection, but these increases were also attenuated by treatment with TY-51469. Plasma aspartate aminotransferase and alanine aminotransferase activities were significantly increased after LPS/GalN injection in the placebo-treated group, but the increases were significantly attenuated in the TY-51469-treated group. The area of hepatic necrotic after LPS/GalN injection was significantly reduced by treatment with TY-51469. Treatment with TY-51469 resulted in significant reductions in the hepatic malondialdehyde concentration, mast cell numbers, and gene expressions of interleukin-1β and myeloperoxidase. Discussion: Chymase inhibition could be a useful strategy to attenuate LPS/GalN-induced ALF in hamsters.
A Case of Pulmonary Infiltrates in a Patient with Colon Carcinoma
Authors: Turner J.F. , Quan W. , Zarogoulidis P. , Browning R.F.
Published: January 2014

A 31-year-old white male with a known history of colon carcinoma was referred to the Interventional Pulmonary service for right lower lobe infiltrates and mucous plugging on computed tomography with concern for pneumonia. Bronchoscopy was performed revealing a broad based mass completely obstructing the bronchus intermedius. It was possible to pass a probe into the right lower lobe, and subsequent photoablation and mechanical debulking revealed that the mass was arising near the origin of the superior basal segment of the right lower lobe (RB6) and could be resected. Pathology confirmed this was consistent with the patient's known primary colon carcinoma. The potential for endobronchial metastasis in patients with colorectal carcinoma should be investigated in those patients with new or worsening pulmonary symptoms and signs.
A Case of a Giant Growing Serous Cystic Neoplasm of the Pancreas
Authors: Kawaguchi Yoshiaki , Nakajima Takayuki , Kawashima Yohei , Maruno Atsuko , Ito Hiroyuki , Ogawa Masami , Mine Tetsuya , Izumi Hideki , Furukawa Daisuke , Yazawa Naoki , Nakagohri Toshio , Hirabayashi Kenichi
Published: January 2014

Because of the widespread use of diagnostic imaging in recent years, serous cystic neoplasm (SCN) of the pancreas can often be detected even when small in diameter. SCNs are usually benign, but it is important to differentiate them from other types of cystic tumors. We report a case of a giant growing SCN that posed a challenge in differential diagnosis.
Carcinomatous Myelitis and Meningitis after a Squamous Cell Carcinoma of the Lip
Authors: Pougnet Isabelle , Murati Anne , Sarran Anthony , Viens Patrice , Sabatier Renaud
Published: January 2014

Background: Nervous central system metastases from head and neck squamous cell carcinoma (SCC) are rare. We report an exceptional case of isolated leptomeningeal and spinal cord involvement few years after the diagnosis of invasive SCC of the lip. Case Report: A 33-year-old man with a history of infracentimetric carcinoma of the lip developed back pain associated with progressive neurological disorders leading to paraplegia. This atypical presentation led to initial misdiagnosis, but radiological and cytological explorations finally confirmed the diagnosis of leptomeningeal and intramedullar secondary spinal cord lesions from his previously treated head and neck SCC. Systemic targeted therapy with epidermal growth factor receptor inhibitor and intrathecal chemotherapy led to prolonged disease stabilization. Conclusion: To our knowledge, this is the first case of isolated neurological metastases from a head and neck SCC. Combination of systemic targeted therapy and intrathecal chemotherapy may be effective in such cases.
A novel approach to assess the spontaneous gastrointestinal bleeding risk of antithrombotic agents using Apc
min/+ mice
Authors: Wei Huijun , Shang Jin , Keohane CarolAnn , Wang Min , Li Qiu , Ni Weihua , O’Neill Kim , Chintala Madhu
Published: January 2014

Assessment of the bleeding risk of antithrombotic agents is usually performed in healthy animals with some form of vascular injury to peripheral organs to induce bleeding. However, bleeding observed in patients with currently marketed antithrombotic drugs is typically spontaneous in nature such as intracranial haemorrhage (ICH) and gastrointestinal (GI) bleeding, which happens most frequently on top of preexisting pathologies such as GI ulcerations and polyps. Apc
min/+ mice are reported to develop multiple adenomas through the entire intestinal tract and display progressive anaemia. In this study, we evaluated the potential utility of Apc
min/+ mice as a model for assessing spontaneous GI bleeding with antithrombotic agents. Apc
min/+ mice exhibited progressive blood loss starting at the age of nine weeks. Despite the increase in bleeding, Apc
min/+ mice were in a hypercoagulable state and displayed an age-dependent increase in thrombin generation and circulating fibrinogen as well as a significant decrease in clotting times. We evaluated the effect of warfarin, dabigatran etexilate, apixaban and clopidogrel in this model by administering them in diet or in the drinking water to mice for 1–4 weeks. All of these marketed drugs significantly increased GI bleeding in Apc
min/+ mice, but not in wild-type mice. Although different exposure profiles of these antithrombotic agents make it challenging to compare the bleeding risk of compounds, our results indicate that the Apc
min/+ mouse may be a sensitive preclinical model for assessing the spontaneous GI bleeding risk of novel antithrombotic agents.
Ribosomal Protein L13a Deficiency in Macrophages Promotes Atherosclerosis by Limiting Translation Control-Dependent Retardation of Inflammation
Authors: Basu Abhijit , Poddar Darshana , Robinet Peggy , Smith Jonathan D. , Febbraio Maria , Baldwin William M. , Mazumder Barsanjit
Published: January 2014

Objective—

Unresolved inflammatory response of macrophages plays a pivotal role in the pathogenesis of atherosclerosis. Previously we showed that ribosomal protein L13a-dependent translational silencing suppresses the synthesis of a cohort of inflammatory proteins in monocytes and macrophages. We also found that genetic abrogation of L13a expression in macrophages significantly compromised the resolution of inflammation in a mouse model of lipopolysaccharide-induced endotoxemia. However, its function in the pathogenesis of atherosclerosis is not known. Here, we examine whether L13a in macrophage has a protective role against high-fat diet–induced atherosclerosis.

Approach and Results—

We bred the macrophage-specific L13a knockout mice L13a Flox
+/+
Cre
+/+
onto apolipoprotein E–deficient background and generated the experimental double knockout mice L13a Flox
+/+
Cre
+/+
apolipoprotein E deficient (apoE
−/−
). L13a Flox
+/+
Cre
−/−
mice on apolipoprotein E–deficient background were used as controls. Control and knockout mice were subjected to high-fat diet for 10 weeks. Evaluation of aortic sinus sections and entire aorta by en face showed significantly higher atherosclerosis in the knockout mice. Severity of atherosclerosis in knockout mice was accompanied by thinning of the smooth muscle cell layer in the media, larger macrophage area in the intimal plaque region and higher plasma levels of inflammatory cytokines. In addition, macrophages isolated from knockout mice had higher polyribosomal abundance of several target mRNAs, thus showing defect in translation control.

Conclusions—

Our data demonstrate that loss of L13a in macrophages increases susceptibility to atherosclerosis in apolipoprotein E–deficient mice, revealing an important role of L13a-dependent translational control as an endogenous protection mechanism against atherosclerosis.
Subclinical Atherosclerosis in Systemic Lupus Erythematosus and Antiphospholipid Syndrome
Authors: Conti Fabrizio , Spinelli Francesca Romana , Alessandri Cristiano , Pacelli Massimo , Ceccarelli Fulvia , Marocchi Elisa , Montali Anna , Capozzi Antonella , Buttari Brigitta , Profumo Elisabetta , Sorice Maurizio , Arca Marcello , Valesini Guido , Riganò Rachele
Published: January 2014

Objective—

Systemic Lupus Erythematosus (SLE) and antiphospholipid syndrome (APS) are associated with a high prevalence of atherosclerosis. β2 glycoprotein I (β2GPI) represents a link between autoimmunity and endothelial dysfunction. Recently, β2GPI reactive T cells have been identified; however, their role in atherosclerosis is still under investigation. We evaluated early atherosclerosis in patients with SLE and APS and investigated T cell reactivity to β2GPI and its relationship with atherosclerotic process.

Approach and Results—

Fifty SLE, 18 patients with primary APS (PAPS), and 25 healthy controls were enrolled. Demographic and clinical data, including traditional cardiovascular risk factors, were recorded. Monocyte β2GPI and Tissue Factor (TF) expression and peripheral blood mononuclear cell response to β2GPI stimulation were evaluated. Doppler ultrasound was performed to investigate flow-mediated dilatation (FMD) and carotid intima-media thickness (IMT). We detected an increase in mean IMT and a decrease in FMD in patients with SLE versus controls (
P
<0.05 and
P
=0.0001, respectively) and a decrease in FMD in patients with PAPS versus controls (
P
<0.05). Monocyte β2GPI and TF expression was higher in patients with SLE and PAPS than in controls (
P
=0.006 and
P
=0.001, respectively); no correlation of monocyte β2GPI and TF with IMT or FMD was detected. β2GPI induced peripheral blood mononuclear cell proliferation in 32% of patients with SLE, 25% of patients with PAPS yet in none of the controls. Proliferative response to β2GPI correlated with a history of arterial thrombosis, thrombocytopenia, and IMT >0.9 mm.

Conclusions—

A significant percentage of patients with SLE and PAPS show a β2GPI-specific T cell reactivity, which is associated with subclinical atherosclerosis.
Microvesicles as Cell–Cell Messengers in Cardiovascular Diseases
Authors: Loyer Xavier , Vion Anne-Clémence , Tedgui Alain , Boulanger Chantal M.
Published: January 2014

Cell–cell communication has proven to be even more complex than previously thought since the discovery that extracellular vesicles serve as containers of biological information on various pathophysiological settings. Extracellular vesicles are classified into exosomes, microvesicles/microparticles, or apoptotic bodies, originating from different subcellular compartments. The cellular machinery controlling their formation and composition, as well as the mechanisms regulating their extracellular release, remain unfortunately much unknown. Extracellular vesicles have been found in plasma, urine, saliva, and inflammatory tissues. Their biomarker potential has raised significant interest in the cardiovascular field because the vesicle composition and microRNA content are specific signatures of cellular activation and injury. More than simply cell dust, extracellular vesicles are capable of transferring biological information to neighboring cells and play an active role in inflammatory diseases, including atherosclerosis and angiogenesis. The molecular interactions regulating these effects involve specific receptor activation, proteolytic enzymes, reactive oxygen species, or delivery of genetic information to target cells. Unraveling their mechanisms of action will likely open new therapeutic avenues.
Exosomes and Cardiac Repair After Myocardial Infarction
Authors: Sahoo Susmita , Losordo Douglas W.
Published: January 2014

Myocardial infarction is a leading cause of death among all cardiovascular diseases. The analysis of molecular mechanisms by which the ischemic myocardium initiates repair and remodeling indicates that secreted soluble factors are key players in communication to local and distant tissues, such as bone marrow. Recently, actively secreted membrane vesicles, including exosomes, are being recognized as new candidates with important roles in intercellular and tissue-level communication. In this review, we critically examine the emerging role of exosomes in local and distant microcommunication mechanisms after myocardial infarction. A comprehensive understanding of the role of exosomes in cardiac repair after myocardial infarction could bridge a major gap in knowledge of the repair mechanism after myocardial injury.
An Adaptive Multi-Swarm Optimizer for Dynamic Optimization Problems
Authors: Li Changhe , Yang Shengxiang , Yang Ming
Published: January 2014

The multipopulation method has been widely used to solve dynamic optimization problems (DOPs) with the aim of maintaining multiple populations on different peaks to locate and track multiple changing optima simultaneously. However, to make this approach effective for solving DOPs, two challenging issues need to be addressed. They are how to adapt the number of populations to changes and how to adaptively maintain the population diversity in a situation where changes are complicated or hard to detect or predict. Tracking the changing global optimum in dynamic environments is difficult because we cannot know when and where changes occur and what the characteristics of changes would be. Therefore, it is necessary to take these challenging issues into account in designing such adaptive algorithms. To address the issues when multipopulation methods are applied for solving DOPs, this paper proposes an adaptive multi-swarm algorithm, where the populations are enabled to be adaptive in dynamic environments without change detection. An experimental study is conducted based on the moving peaks problem to investigate the behavior of the proposed method. The performance of the proposed algorithm is also compared with a set of algorithms that are based on multipopulation methods from different research areas in the literature of evolutionary computation.
Cocconeis pinnata W. Gregory ex Greville (Bacillariophyta): Lectotypification and an emended description after examination of type material and South Pacific specimens
Authors: Riaux-Gobin Catherine , COMPÈRE PIERRE , ROMERO OSCAR E. , WILLIAMS DAVID M.
Published: January 2014

A marine species of Cocconeis (Bacillariophyta) from coral reef lagoon of Tahiti Island (Society Archipelago, South Pacific) was identified as Cocconeis pinnata W. Gregory ex Greville. Neither drawings nor micrographs of the raphe valve (RV) of C. pinnata are available in the literature. The examination of Gregory's type material (several slides annotated 'Arran 57' from Greville's collection housed in BM, British Museum, London, U.K.) allowed us to complete and emend the C. pinnata description. Lectotypification of C. pinnata is proposed. Since the raw material used by Gregory was not found, no scanning electron microscope (SEM) observation of type material can be provided. Except for Hustedt (1933) and a few later reports, all descriptions and illustrations agree with the original description. LM and SEM observations demonstrate that the sternum valve (SV) stria arrangement of specimens from Tahiti match those of the type. The description of the RV by Grunow in Van Heurck (1880) refers to a stria pattern very similar to that of C. pseudomarginata W. Gregory. The RV of C. pinnata, as revealed in LM and SEM, has a dense striation and no internal marginal rim. Both valves of C. pinnata have areolae with remarkable arborescent volae, which is a new feature for Cocconeis. Cocconeis pinnata is cosmopolitan, from cold-temperate to tropical areas. Several taxa have been formerly assigned to C. pinnata, though they are probably varieties of C. costata.
Dendrodontia hyphopaxillosa (Basidiomycota, Polyporaceae), a new species with dense hyphal pegs from southern China
Authors: Li Mengjie , Yuan Haisheng
Published: January 2014

Dendrodontia hyphopaxillosa, a new epithelioid species from southern China in Polyporaceae is described and illustrated. The species is characterized by resupinate, adnate, effused basidiocarps, densely distributed cylindrical hyphal pegs, frequently branched contorted dendrohyphidia and small ellipsoid to subcylindrical basidiospores. Discriminating characters between the new species and closely related species are discussed, and an identification key to the species of Dendrodontia is provided.
Two new tardigrade species from Sicily
Authors: PILATO GIOVANNI , SABELLA GIORGIO , LISI OSCAR
Published: January 2014

Two new species of tardigrades are described from Sicilian moss samples: Macrobiotus insuetus sp. nov. and Diphascon (Diphascon) procerum sp. nov.        Macrobiotus insuetus sp. nov. is a species of the harmsworthi-group characterized by both posterior and anterior claws of the hind legs, which are different in shape from those of the first three leg pairs. The IV claws have extended basal tract where the branches are joined and the secondary branch breaks at near right angle to the primary branch and is clearly shorter than the main branch and the secondary branch of claws I-III. The eggs are not areolated and have conical processes with a reticular ornamentation.        Diphascon (D.) procerum sp. nov. has a delicate cuticular ornamentation of very small tubercles, almost dots; two macroplacoids and septulum are present; thin accessory points are present on the main branches of the slender claws; lunules are absent but the base of the external claws of the hind legs are enlarged and slightly indented; a cuticular bar is present near the internal claw of the first three leg pairs and two cuticular bars are present on the hind legs between the base of the claws and near the base of the anterior claw.
Correcting the disconnect between phylogenetics and biodiversity informatics
Authors: MILLER JOSEPH T. , JOLLEY-ROGERS GARRY
Published: January 2014

Rich collections of biodiversity data are now synthesized in publically available databases and phylogenetic knowledge now provides a sound understanding of the origin of organisms and their place in the tree of life. However, these knowledge bases are poorly linked, leading to underutilization or worse, an incorrect understanding of biodiversity because there is poor evolutionary context. We address this problem by integrating biodiversity information aggregated from many sources onto phylogenetic trees. PhyloJIVE connects biodiversity and phylogeny knowledge bases by providing an integrated evolutionary view of biodiversity data which in turn can improve biodiversity research and the conservation decision making process. Biodiversity science must assert the centrality of evolution to provide effective data to counteract global change and biodiversity loss.
Apterogyninae (Hymenoptera: Bradynobaenidae) from Saudi Arabia, with description of a new species
Authors: GADALLAH NEVEEN S. , DHAFER HATHAL M. AL , ALDRYHIM YOUSIF N. , FADL HASSAN , ELGHARBAWY ALI A. , PAGLIANO GUIDO
Published: January 2014

Eleven species in three genera from Saudi Arabia are listed. Macroocula riyadha Gadallah & Pagliano, spec. nov. is described and figured. Apterogyna mateui Giner Marí, 1945, Macroocula nitida nitida (Bischoff, 1920) are newly recorded from Arabian Peninsula and Saudi Arabia, Macroocula magna (Invrea, 1965) is newly recorded from Saudi Arabia.
Reproductive biology of galatheoid and chirostyloid (Crustacea: Decapoda) squat lobsters from the Gulf of Mexico
Authors: Kilgour Morgan J. , Shirley Thomas C.
Published: January 2014

Reproductive timing, fecundity, and average egg sizes were examined for galatheoid and chirostyloid squat lobster collections from the Gulf of Mexico. While congeners did not always significantly differ in egg size or timing, each genus had a unique average egg diameter size which may indicate whether the developing embryos will be lecithotrophic or planktotrophic larvae. The eggs of Eumunididae, Galatheidae, and Munididae were more numerous and smaller than the larger and less abundant eggs of Chirostylidae and Munidopsidae. With the exception of members of the Munididae, members of genera within the same family had distinct egg diameters. Ovigerous females were significantly larger than non-ovigerous females in some species (i.e., Uroptychus nitidus, Munida forceps, Galacantha spinosa, Munidopsis abbreviata, M. alaminos, M., erinacea, M. robusta, M. sigsbei, and M. simplex). Munidopsis erinacea and Munida affinis males were significantly larger than females; the reverse was true for Munidopsis robusta and Munidopsis simplex. All other species studied did not have a significant difference between males and females. The spatial and bathymetric ranges for many species are extended in this study from prior reports. Seasonality of reproduction was evident in few species, but this may be a result of limited sample sizes.
Initial Transient Response of the Winter Polar Stratospheric Vortex to Idealized Equatorial Pacific Sea Surface Temperature Anomalies in the NCAR WACCM
Authors: Hegyi Bradley M. , Deng Yi , Black Robert X. , Zhou Renjun
Published: January 2014

Perpetual winter simulations using the NCAR Whole Atmosphere Community Climate Model (WACCM) are conducted to document the differences of the initial transient response of the boreal winter Northern Hemisphere stratospheric polar vortex to central (CPW) and eastern Pacific warming (EPW) events. Idealized patches of positive sea surface temperature (SST) anomalies are superimposed onto a climatological SST field to mimic canonical CPW and EPW forcings. A 20-member ensemble was created by varying initial atmospheric conditions for both CPW and EPW cases. In the ensemble average, the vortex weakens under both CPW and EPW forcing, indicated by a negative zonal mean zonal wind tendency. This tendency is mainly tied to changes in the eddy-driven mean meridional circulation (MMC). A negative anomaly in the eddy momentum flux convergence also plays a secondary role in the weakening. The vortex response, however, differs dramatically among individual ensemble members. A few ensemble members exhibit initial vortex strengthening although weaker in magnitude and shorter in duration than the initial weakening in the ensemble average. The initial state and the subsequent internal variation of the extratropical atmosphere is at least as important as the type of SST forcing in determining the transient response of the stratospheric polar vortex. Interactions between the internal variability of the vortex and SST-driven wave anomalies ultimately determine the nature of the initial transient response of the vortex to EPW and CPW forcing. This sensitivity to the initial atmospheric state has implications for understanding medium-range forecasts of the extratropical atmospheric response to emerging tropical SST anomalies, particularly over high-latitude regions.
Profiling Sea Ice with a Multiple Altimeter Beam Experimental Lidar (MABEL)
Authors: Kwok R. , Markus T. , Morison J. , Palm S. P. , Neumann T. A. , Brunt K. M. , Cook W. B. , Hancock D. W. , Cunningham G. F.
Published: January 2014

The sole instrument on the upcoming Ice, Cloud, and Land Elevation Satellite (ICESat-2) altimetry mission is a micropulse lidar that measures the time of flight of individual photons from laser pulses transmitted at 532 nm. Prior to launch, the Multiple Altimeter Beam Experimental Lidar (MABEL) serves as an airborne implementation for testing and development. This paper provides a first examination of MABEL data acquired on two flights over sea ice in April 2012: one north of the Arctic coast of Greenland and the other in the east Greenland Sea. The phenomenology of photon distributions in the sea ice returns is investigated. An approach to locate the surface and estimate its elevation in the distributions is described, and its achievable precision is assessed. Retrieved surface elevations over relatively flat leads in the ice cover suggest that precisions of several centimeters are attainable. Restricting the width of the elevation window used in the surface analysis can mitigate potential biases in the elevation estimates due to subsurface returns at 532 nm. Comparisons of nearly coincident elevation profiles from MABEL with those acquired by an analog lidar show good agreement. Discrimination of ice and open water, a crucial step in the determination of sea ice freeboard and the estimation of ice thickness, is facilitated by contrasts in the observed signal–background photon statistics. Future flight paths will sample a broader range of seasonal ice conditions for further evaluation of the year-round profiling capabilities and limitations of the MABEL instrument.
A 4DVAR System for the Navy Coastal Ocean Model. Part I: System Description and Assimilation of Synthetic Observations in Monterey Bay*
Authors: Ngodock Hans , Carrier Matthew
Published: January 2014

A 4D variational data assimilation system was developed for assimilating ocean observations with the Navy Coastal Ocean Model. It is described in this paper, along with initial assimilation experiments in Monterey Bay using synthetic observations. The assimilation system is tested in a series of twin data experiments to assess its ability to fit assimilated and independent observations by controlling the initial conditions and/or the external forcing while assimilating surface and/or subsurface observations. In all strong and weak constraint experiments, the minimization of the cost function is done with both the gradient descent method (in the control space) and the representer method (observation space). The accuracy of the forecasts following the analysis and the relevance of the retrieved forcing correction in the case of weak constraints are evaluated. It is shown that the assimilation system generally fits the assimilated and nonassimilated observations well in all experiments, yielding lower forecast errors.
The Early Robin Hood and “The Myght of Mylde Marye”
Authors: Carroll Michael P.
Published: January 2014

A number of reformist commentators in late medieval England suggested that stories about Robin Hood were especially popular with people who were not especially devout. On the other hand, notwithstanding these reformist comments, we also have evidence that Robin Hood stories were sometimes used as sermon exempla, which suggests that they were seen (at least by some preachers) as promoting acceptable forms of Catholic devotion. At one level, the use of these stories as sermon exempla derived from the fact that in these early stories (quite unlike later stories) Robin was depicted as committed to the Mass and devoted to the Virgin Mary. The real value of these early stories about Robin Hood, however, is that they allow us to problematize two historiographical assumptions that continue to guide the thinking of English historians studying late medieval Catholicism. Thus, English historians (including the revisionist historians who have otherwise done so much to document the vitality of English Catholicism on the eve of the Reformation) continue to mimic official Catholic doctrine in suggesting that for English Catholics, Christ was the supernatural being who stood atop the Catholic pantheon, and that Mary and the saints were viewed only as intercessors with no independent power of their own. By contrast, the evidence from the Robin Hood stories (and from other stories used as sermon exempla) very explicitly depicts a rank ordering in which Mary not only had independent power, but independent power which eclipsed that of her Son.
Measles in Scotland, 2013
Authors: Pollock K , Potts A , Love J , Steedman N , Donaghy M
Published: January 2014

In 2013, Wales and England experienced large outbreaks of measles, a disease that has been targeted by the World Health Organisation for European elimination by 2015. Unfortunately, measles-mumps-rubella vaccine uptake declined to less than 80% in Wales and England after the Wakefield publicity and this resulted in increased population susceptibility to measles. In Scotland, measles-mumps-rubella vaccine uptake dropped to 87% in 2003. Scottish public health efforts in response to this decline aimed to maximise uptake of MMR1 by two years; ensure at least 95% uptake of one dose of measles-mumps-rubella before starting school at age five; and maximise uptake of the second dose of measles-mumps-rubella by age six. Although Scotland has not had any large outbreaks reported to date, transmission of measles from healthcare workers to patients has occurred and reiterates the importance of all healthcare workers accurately knowing their immune status and, when needed, to be fully immunised.