bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of Stress Granules and P Bodies during Dicistrovirus Infection
Authors: Khong Anthony , Jan Eric 
Published: November 2010

ABSTRACTStress granules (SGs) are dynamic cytosolic aggregates composed of ribonucleoproteins that are induced during cellular stress when protein synthesis is inhibited. The function of SGs is poorly understood, but they are thought to be sites for reorganizing mRNA and protein. Several viruses can modulate SG formation, suggesting that SGs have an impact on virus infection. In this study, we have investigated the relationship of SG formation inDrosophilaS2 cells infected by cricket paralysis virus (CrPV), a member of theDicistroviridaefamily. Despite a rapid shutoff of host translation during CrPV infection, several hallmark SG markers such as theDrosophilaTIA-1 and G3BP (RasGAP-SH3-binding protein) homologs, Rox8 and Rin, respectively, do not aggregate in CrPV-infected cells, even when challenged with potent SG inducers such as heat shock, oxidative stress, and pateamine A treatment. Furthermore, we demonstrate that a subset of P body markers become moderately dispersed at late times of infection. In contrast, as shown by fluorescentin situhybridization, poly(A)+RNA granules still form at late times of infection. These poly(A)+RNA granules do not contain viral RNA nor do they colocalize with P body markers. Finally, our results demonstrate that the CrPV viral 3C protease is sequestered to SGs under cellular stress but not during virus infection. In summary, we propose that dicistrovirus infection leads to the selective inhibition of distinct SGs so that viral proteins are available for viral processing.
Emergency presentations of Parkinson's disease: early recognition and treatment are crucial for optimum outcome
Authors: Ghosh R , Liddle B J 
Published: November 2010

ABSTRACT
Parkinson's disease (PD) is a debilitating condition associated with significant morbidity and mortality. Pathophysiologically the illness is due to a disruption of dopamine production in the basal ganglia and leads to a wide array of symptoms. These symptoms are not restricted to the nervous system; thus, the illness often presents acutely to a wide range of specialties, many of which may have limited experience in the condition. Patients often become unwell with illnesses unrelated to their PD. However, these conditions frequently lead to a deterioration in PD control. In addition, there exist certain acute complications of PD which are often difficult to recognise and carry significant mortality. Discussing the acute presentations of the illness under the umbrella of PD is important as it enables clinicians to focus upon the specific concerns involved in managing patients with the illness. A number of conditions are extremely common in PD and include falls, orthostatic hypotension, swallowing difficulties, psychosis, and hyperkinetic movement disorders. Optimal treatment of these conditions requires the consideration of issues specific to PD. Lesser recognised acute presentations of PD include the serotonin syndrome and neuroleptic malignant-like syndrome. While encountered less commonly, these conditions have been well described in the literature and untreated may prove fatal. They require urgent management, with their importance being further highlighted by the fact they may often mimic other illnesses, making diagnosis difficult. Therapeutic interventions aimed at treating PD and preventing its complications are evolving rapidly.
Smoking among Lao medical doctors: challenges and opportunities for tobacco control
Authors: Vanphanom Sychareun , Morrow Martha , Phengsavanh Alongkone , Hansana Visanou , Phommachanh Sysavanh , Tomson Tanja 
Published: November 2010

BackgroundSmoking is an increasing threat to health in low-income and middle-income countries and doctors are recognised as important role models in anti-smoking campaigns.ObjectivesThe study aimed to identify the smoking prevalence of medical doctors in Laos, their tobacco-related knowledge and attitudes, and their involvement in and capacity for tobacco prevention and control efforts.MethodsThis was a cross-sectional national survey by a researcher-administered, face-to-face questionnaire implemented at provincial health facilities throughout the central (including national capital), northern and southern regions of Laos in 2007. Both descriptive and inferential statistics were used.ResultsOf the 855 participants surveyed, 9.2% were current smokers and 18.4% were ex-smokers; smoking was least common in the central region (p<0.05) and far more prevalent in males (17.3% vs 0.4%; p<0.001). Smoking was concentrated among older doctors (p <0.001). Over 84% of current smokers wanted to quit, and 74.7% had made a recent serious attempt to do so. Doctors had excellent knowledge and positive attitudes to tobacco control, although smokers were relatively less knowledgeable and positive on some items. While 78% of doctors were engaged in cessation support, just 24% had been trained to do so, and a mere 8.8% considered themselves ‘well prepared’.ConclusionThe willingness of doctors to take up their tobacco control role and the lower smoking rates among younger respondents offers an important window of opportunity to consolidate their knowledge, attitudes, skills and enthusiasm as cessation advocates and supports.
Vandetanib Improves Anti-Tumor Effects of L19mTNFα in Xenograft Models of Esophageal Cancer
Authors: Crescenzi Marika , Persano Luca , Esposito Giovanni , Zulato Elisabetta , Borsi Laura , Balza Enrica , Ruol Alberto , Ancona Ermanno , Indraccolo Stefano , Amadori Alberto 
Published: November 2010

AbstractPurpose: Targeting the tumor vasculature by vascular disrupting agents (VDAs) has shown therapeutic activity in mouse models. In most cases, however, VDA efficacy is substantially compromised by the inability of these drugs to completely kill tumor cells located at the periphery of the tumor mass. In this study, we investigated anti-tumor effects of L19mTNFα, a fusion protein composed of L19 (scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform, and murine TNFα, in xenograft models of esophageal cancer.Experimental design: We evaluated ED-B expression in esophageal cancer samples. Subsequently, we generated subcutaneous xenografts from primary tumors, treated them with the L19mTNFα scFv, and determined effects on tumor vasculature, viability and proliferation, and VEGF expression and infiltration by hematopoietic cells. To overcome tumor resistance, L19mTNFα scFv was combined with vandetanib, a tyrosine kinase inhibitor of VEGF receptor, epidermal growth factor receptor, and RET signaling.Results: ED-B was broadly expressed by esophageal cancer cell lines, as well as xenografts and primary surgical samples of esophageal cancer. Administration of L19mTNFα acutely damaged tumor vasculature and increased necrosis, indicating a VDA-like activity of this immunoconjugate. This event was followed, however, by rapid tumor growth recovery associated with increased expression of VEGF and recruitment of CD11b+Gr1+ myeloid cells into tumors. Combination of L19mTNFα with vandetanib severely impaired vascular functions in tumors, leading to a reduction of cell proliferation and increased necrosis, without apparent signs of toxicity.Conclusion: These findings indicate that a combination of vascular damaging agents with anti-angiogenic drugs could represent a promising therapeutic strategy for esophageal cancer. Clin Cancer Res; 17(3); 447–58. ©2010 AACR.
Tumor Regression and Growth Rates Determined in Five Intramural NCI Prostate Cancer Trials: The Growth Rate Constant as an Indicator of Therapeutic Efficacy
Authors: Stein Wilfred D. , Gulley James L. , Schlom Jeff , Madan Ravi A. , Dahut William , Figg William D. , Ning Yang-min , Arlen Phil M. , Price Doug , Bates Susan E. , Fojo Tito 
Published: November 2010

Abstract
Purpose: In solid tumors such as prostate cancer, novel paradigms are needed to assess therapeutic efficacy. We utilized a method estimating tumor growth and regression rate constants from serial PSA measurements, and assessed its potential in patients with metastatic castration resistant prostate carcinoma (mCRPC).
Experimental Design: Patients were enrolled in five phase II studies, including an experimental vaccine trial, representing the evolution of therapy in mCRPC. PSA measurements obtained before, and during, therapy were used. Data analysis using a two-phase mathematical equation yielded concomitant PSA growth and regression rate constants.
Results: Growth rate constants (g) can be estimated while patients receive therapy and in such patients g is superior to PSA-DT in predicting OS. Incremental reductions in growth rate constants were recorded in successive trials with a 10-fold slower g in the most recent combination therapy trial (log g = 10−3.17) relative to single-agent thalidomide (log g = 10−2.08) more than a decade earlier. Growth rate constants correlated with survival, except in patients receiving vaccine-based therapy where the evidence demonstrates prolonged survival presumably due to immunity developing subsequent to vaccine administration.
Conclusion: Incremental reductions in tumor growth rate constants suggest increased efficacy in successive chemotherapy trials. The derived growth rate constant correlates with survival, and may be used to assess efficacy. The PSA-TRICOM vaccine appears to have provided marked benefit not apparent during vaccination, but consistent with subsequent development of a beneficial immune response. If validated as a surrogate for survival, growth rate constants would offer an important new efficacy endpoint for clinical trials. Clin Cancer Res; 17(4); 907–17. ©2010 AACR.
A Phase I Study of the Combination of Intravenous Reovirus Type 3 Dearing and Gemcitabine in Patients with Advanced Cancer
Authors: Lolkema Martijn P. , Arkenau Hendrik-Tobias , Harrington Kevin , Roxburgh Patricia , Morrison Rosemary , Roulstone Victoria , Twigger Katie , Coffey Matt , Mettinger Karl , Gill George , Evans T.R. Jeffry , de Bono Johann S. 
Published: November 2010

Abstract
Purpose: This study combined systemic administration of the oncolytic reovirus type 3 Dearing (reovirus) with chemotherapy in human subjects. We aimed to determine the safety and feasibility of combining reovirus administration with gemcitabine and to describe the effects of gemcitabine on the antireoviral immune response.
Experimental Design: Patients received reovirus in various doses, initially we dosed for five consecutive days but this was poorly tolerated. We amended the protocol to administer a single dose and administered up to 3 × 1010 TCID50. Toxicity was assessed by monitoring of clinical and laboratory measurements. We assessed antibody response by cytotoxicity neutralization assay.
Results: Sixteen patients received 47 cycles of reovirus. The two initial patients and one patient in the final cohort experienced dose limiting toxicity (DLT). The DLTs consisted of two asymptomatic grade 3 liver enzyme rises and one asymptomatic grade 3 troponin I rise. Common toxicities consisted of known reovirus and gemcitabine associated side effects. Further analysis showed a potential interaction between reovirus and gemcitabine in causing liver enzyme rises. Grade 3 rises in liver enzymes were associated with concomitant aminocetophen use. Importantly, the duration of the liver enzyme rise was short and reversible. Neutralizing antibody responses to reovirus were attenuated both in time-to-occurrence and peak height of the response.
Conclusions: Reovirus at the dose of 1 × 1010 TCID50 can be safely combined with full dose gemcitabine. Combination of reovirus with gemcitabine affects the neutralizing antibody response and this could impact both safety and efficacy of this treatment schedule. Clin Cancer Res; 17(3); 581–8. ©2010 AACR.
Extended Dose Ipilimumab with a Peptide Vaccine: Immune Correlates Associated with Clinical Benefit in Patients with Resected High-Risk Stage IIIc/IV Melanoma
Authors: Sarnaik Amod A. , Yu Bin , Yu Daohai , Morelli Dawn , Hall MacLean , Bogle Dilip , Yan Lulu , Targan Stephan , Solomon Jolie , Nichol Geoff , Yellin Michael , Weber Jeffrey S. 
Published: November 2010

Abstract
Purpose: To determine safety and feasibility of adjuvant ipilimumab following resection of high-risk melanoma and to identify surrogate markers for benefit.
Experimental Design: In this phase II trial, 75 patients with resected stage IIIc/IV melanoma received the CTLA-4 antibody ipilimumab every 6 to 8 weeks for 1 year. Eligible patients received further maintenance treatments. The first 25 patients received 3 mg/kg of ipilimumab, and an additional 50 patients received 10 mg/kg. HLA-A*0201+ patients received multipeptide immunizations in combination with ipilimumab. Leukapheresis was performed prior to and 6 months after initiation of treatment.
Results: Median overall and relapse-free survivals were not reached after a median follow-up of 29.5 months. Significant immune-related adverse events were observed in 28 of 75 patients and were positively associated with longer relapse-free survival. Antigen-specific T cell responses to vaccine were variable, and vaccine combination was not associated with additional benefit. No effects on T regulatory cells were observed. Higher changes in Th-17 inducible frequency were a surrogate marker of freedom from relapse (P = 0.047), and higher baseline C-reactive protein (CRP) levels were associated with freedom from relapse (P = 0.035).
Conclusions: Adjuvant ipilimumab following resection of melanoma at high risk for relapse appeared to be associated with improved outcome compared to historical reports. Significant immune-related adverse events were generally reversible and appeared to be associated with improved relapse-free survival. Although vaccination failed to induce a consistent in vitro measurable response, a higher change in Th-17 inducible cells and higher baseline CRP levels were positively associated with freedom from relapse. Clin Cancer Res; 17(4); 896–906. ©2010 AACR.
Blinded by the Light: Molecular Imaging in Pancreatic Adenocarcinoma
Authors: Collisson Eric , Tempero Margaret 
Published: November 2010

Abstract
The early detection and optimal perisurgical management of pancreatic adenocarcinoma are paramount goals in our quest to increase cure rates in this lethal malignancy. Molecular imaging techniques may be the conduit through which new genomic and proteomic discoveries about this disease are brought to the clinic. Clin Cancer Res; 17(2); 203–5. ©2010 AACR.
Telomerase Activation in Atherosclerosis and Induction of Telomerase Reverse Transcriptase Expression by Inflammatory Stimuli in Macrophages
Authors: Gizard Florence , Heywood Elizabeth B. , Findeisen Hannes M. , Zhao Yue , Jones Karrie L. , Cudejko Céline , Post Ginell R. , Staels Bart , Bruemmer Dennis 
Published: November 2010

Objective—
Telomerase serves as a critical regulator of tissue renewal. Although telomerase activity is inducible in response to various environmental cues, it remains unknown whether telomerase is activated during the inflammatory remodeling underlying atherosclerosis formation. To address this question, we investigated in the present study the regulation of telomerase in macrophages and during atherosclerosis development in low-density lipoprotein receptor–deficient mice.

Methods and Results—
We demonstrate that inflammatory stimuli activate telomerase in macrophages by inducing the expression of the catalytic subunit telomerase reverse transcriptase (TERT). Reporter and chromatin immunoprecipitation assays identified a previously unrecognized nuclear factor-κB (NF-κB) response element in the TERT promoter, to which NF-κB is recruited during inflammation. Inhibition of NF-κB signaling completely abolished the induction of TERT expression, characterizing TERT as a bona fide NF-κB target gene. Furthermore, functional experiments revealed that TERT deficiency results in a senescent cell phenotype. Finally, we demonstrate high levels of TERT expression in macrophages of human atherosclerotic lesions and establish that telomerase is activated during atherosclerosis development in low-density lipoprotein receptor–deficient mice.

Conclusion—
These results characterize TERT as a previously unrecognized NF-κB target gene in macrophages and demonstrate that telomerase is activated during atherosclerosis. This induction of TERT expression prevents macrophage senescence and may have important implications for the development of atherosclerosis.
Critical Roles of Macrophages in the Formation of Intracranial Aneurysm
Authors: Kanematsu Yasuhisa , Kanematsu Miyuki , Kurihara Chie , Tada Yoshiteru , Tsou Tsung-Ling , van Rooijen Nico , Lawton Michael T. , Young William L. , Liang Elena I. , Nuki Yoshitsugu , Hashimoto Tomoki 
Published: November 2010

Background and Purpose—
Abnormal vascular remodeling triggered by hemodynamic stresses and inflammation is believed to be a key process in the pathophysiology of intracranial aneurysms. Numerous studies have shown infiltration of inflammatory cells, especially macrophages, into intracranial aneurysmal walls in humans. Using a mouse model of intracranial aneurysms, we tested whether macrophages play critical roles in the formation of intracranial aneurysms.

Methods—
Intracranial aneurysms were induced in adult male mice using a combination of a single injection of elastase into the cerebrospinal fluid and angiotensin II-induced hypertension. Aneurysm formation was assessed 3 weeks later. Roles of macrophages were assessed using clodronate liposome-induced macrophage depletion. In addition, the incidence of aneurysms was assessed in mice lacking monocyte chemotactic protein-1 (CCL2) and mice lacking matrix metalloproteinase-12 (macrophage elastase).

Results—

Intracranial aneurysms in this model showed leukocyte infiltration into the aneurysmal wall, the majority of the leukocytes being macrophages. Mice with macrophage depletion had a significantly reduced incidence of aneurysms compared with control mice (1 of 10 versus 6 of 10;
P
<0.05). Similarly, there was a reduced incidence of aneurysms in mice lacking monocyte chemotactic protein-1 compared with the incidence of aneurysms in wild-type mice (2 of 10 versus 14 of 20,
P
<0.05). There was no difference in the incidence of aneurysms between mice lacking matrix metalloproteinase-12 and wild-type mice.

Conclusions—
These data suggest critical roles of macrophages and proper macrophage functions in the formation of intracranial aneurysms in this model.
Intracranial Large Vessel Occlusion as a Predictor of Decline in Functional Status After Transient Ischemic Attack
Authors: Poisson Sharon N. , Nguyen-Huynh Mai N. , Johnston S. Claiborne , Furie Karen L. , Lev Michael H. , Smith Wade S. 
Published: November 2010

Background and Purpose—
Clinical scores help predict outcome after transient ischemic attack (TIA), and imaging studies may improve the accuracy of predictions. Intracranial large vessel occlusion (LVO) predicts poor outcome after stroke, but the natural history of symptomatic intracranial LVO in patients with TIA is unknown.

Methods—

We studied patients presenting with TIA in the STOP Stroke Study, a prospective imaging-based study of stroke outcomes. All patients underwent brain CTA. If an intracranial vascular occlusion was found in an appropriate territory to account for clinical findings, then it was judged to be a symptomatic LVO. Baseline characteristics, follow-up events, and outcomes were collected. Characteristics of patients with and without LVO were compared using χ
2
and
t
tests. Predictors of LVO were analyzed by univariate and multivariate analysis. LVO was assessed as a predictor of asymptomatic outcome (modified Rankin scale [mRS] score, 0), poor outcome (mRS score ≤3), and increase in mRS score over the study period.

Results—

Of 97 patients with TIA, 13 (13%) had symptomatic intracranial LVO. Patients with LVO had higher baseline NIHSS on emergency department arrival, which was an independent predictor of LVO (OR, 1.15 per point; 95% CI, 1.02–1.29;
P
=0.02). Patients with LVO were more likely to have an increase in mRS score during the 90-day follow-up (
P
=0.03). LVO independently predicted an increase in mRS score (OR, 4.76; 95% CI, 1.23–18.43;
P
=0.02) and was a borderline predictor of poor outcome (mRS score ≥3; OR, 5.07; 95% CI, 0.92–28.03;
P
=0.06).

Conclusions—
LVO is found in >1 in 10 patients presenting with TIA and predicts a decline in functional status, likely attributable to new brain ischemia.
Myeloid-Specific Deletion of the Mineralocorticoid Receptor Reduces Infarct Volume and Alters Inflammation During Cerebral Ischemia
Authors: Frieler Ryan A. , Meng He , Duan Sheng Zhong , Berger Stefan , Schütz Günther , He Yangdong , Xi Guohua , Wang Michael M. , Mortensen Richard M. 
Published: November 2010

Background and Purpose—
Mineralocorticoid receptor (MR) antagonists have protective effects in rodent models of ischemic stroke, but the cell type-specific actions of these drugs are unknown. In the present study, we examined the contribution of myeloid cell MR during focal cerebral ischemia using myeloid-specific MR knockout mice.

Methods—
Myeloid-specific MR knockout mice were subjected to transient (90 minutes) middle cerebral artery occlusion followed by 24 hours reperfusion (n=5 to 7 per group). Ischemic cerebral infarcts were identified by hematoxylin and eosin staining and quantified with image analysis software. Immunohistochemical localization of microglia and macrophages was performed using Iba1 staining, and the expression of inflammatory markers was measured after 24 hours of reperfusion by quantitative reverse transcription–polymerase chain reaction.

Results—

Myeloid-specific MR knockout resulted in a 65% reduction in infarct volume (
P
=0.005) after middle cerebral artery occlusion. This was accompanied by a significant reduction in activated microglia and macrophages in the ischemic core. Furthermore, myeloid-specific MR knockout suppressed classically activated M1 macrophage markers tumor necrosis factor-α, interleukin-1β, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and interleukin-6 at the same time as partially preserving the induction of alternatively activated, M2, markers Arg1, and Ym1.

Conclusions—
These data demonstrate that myeloid MR activation exacerbates stroke and identify myeloid MR as a critical target for MR antagonists. Furthermore, these data indicate that MR activation has an important role in controlling immune cell function during the inflammatory response to stroke.
Is Levinas’s Philosophy a Response to the Holocaust?
Authors: Shaw Joshua 
Published: November 2010

AbstractSome commentators have claimed that Emmanuel Levinas’s philosophy should be understood as a response to the Holocaust. This study assesses that claim. It begins by clarifying what it means to call his philosophy a “response.” The bulk of the article then analyzes his essay, “Useless Suffering,” one of the few works in Levinas’s philosophic oeuvre where he discusses the Holocaust. Levinas is widely read as claiming that there can be no explanation for the Holocaust—that it marks “the end of theodicy.” It is shown, however, that his point is not that it cannot be explained, but that we misjudge the nature of evil when we view it as calling for explanation rather than practical activity. Based on this analysis, it is argued that Levinas’s philosophy can be understood as a response to the Holocaust in the sense of being a performative writing that sought to address the evil that occurred in the Holocaust by transforming the ethical sensibilities of his readers.