bluuebunny/crossref_metadata_2025_split huggingface dataset:
What Is the Role of Radiotherapy in Malignant Pleural Mesothelioma?
Authors: Price Allan 
Published: February 2011

Abstract

Objective.
A review of the evidence supporting the use of radiotherapy in patients with mesothelioma was performed.

Methods.
Relevant publications were searched for on Medline.

Results.
In a Medline search on radiotherapy and mesothelioma, 611 hits were obtained. A limited number of prospective phase II trials of radiotherapy as part of trimodality protocols for early disease and in the palliation of pain were found, along with three small randomized controlled trials of port-site prophylaxis.

Conclusion.
No randomized data exist to support the use of radiotherapy after radical surgery, although there are a large number of publications describing its use as an integral part of therapy, including seven phase II studies. One ongoing trial is randomizing patients to radiotherapy or not after extrapleural pneumonectomy. None of these studies provided any assessment of radiotherapy independent of the other modalities investigated, nor did any formally assess intensity-modulated radiotherapy. There have been several reports of excessive toxicity with this technique, and its use should be limited to phase I studies until the basis of this toxicity is better understood. Three trials have looked at port-site prophylaxis, one supporting its use and two showing no evidence of benefit. Two studies addressed pain control prospectively, one showing definite but short-lived benefits.

Implications.
Radiotherapy is widely used in treating mesothelioma with little supporting evidence. More randomized trials are required to justify this use in all three common settings for its use.
Clinical Relevance of the Dose of Cytarabine in the Upfront Treatment of Primary CNS Lymphomas with Methotrexate-Cytarabine Combination
Authors: Ferreri Andrés J. M. , Licata Giada , Foppoli Marco , Corazzelli Gaetano , Zucca Emanuele , Stelitano Caterina , Zaja Francesco , Fava Sergio , Paolini Rossella , Franzin Alberto , Politi Letterio S. , Ponzoni Maurilio , Reni Michele 
Published: February 2011

Abstract

Background.
The combination of high doses of methotrexate (MTX) and cytarabine (araC) is the standard chemotherapy for patients with primary CNS lymphoma (PCNSL). The addition of an alkylating agent could improve MTX-araC efficacy because it is active against quiescent G0 cells and increases antimetabolites cytotoxicity. A pilot experience with high doses of MTX, araC, and thiotepa (MAT regimen) was performed to investigate feasibility and efficacy of adding an alkylating agent. With respect to MTX-araC combination, araC dose was halved to minimize toxicity. Herein, we report tolerability, activity, and efficacy of MAT regimen and compare these results to those previously reported with MTX/ara-C combination.

Methods.
Twenty HIV-negative patients with PCNSL treated with MAT regimen and whole-brain irradiation and selected according to eligibility criteria of the International Extranodal Lymphoma Study Group (IELSG) #20 trial were analyzed.

Results.
Patient characteristics of MAT and MTX-araC series were similar. G4 hematologic toxicity was common after MAT chemotherapy, with dose reductions in 60% of patients, infections in 20%, G4 non-hematologic toxicity in 15%, and one (5%) toxic death. Response after chemotherapy was complete in four patients (clinical response rate, 20%; 95% confidence interval, 3%–37%) and partial in three (overall response rate, 35%; 95% confidence interval, 15%–55%). Fifteen patients experienced failure and 16 died (median follow-up, 26 months), with a 2-year overall survival of 24% ± 9%.

Conclusions.
MAT and MTX-araC combinations showed similar tolerability, whereas araC dose reduction was associated with a remarkably lower efficacy, hiding any potential benefit of thiotepa. Four doses of araC 2 g/m2 per course are recommended in patients with PCNSL.
Information Metrics in Genetic Epidemiology
Authors: Tritchler David L , Sucheston Lara , Chanda Pritam , Ramanathan Murali 
Published: February 2011

Information-theoretic metrics have been proposed for studying gene-gene and gene-environment interactions in genetic epidemiology. Although these metrics have proven very promising, they are typically interpreted in the context of communications and information transmission, diminishing their tangibility for epidemiologists and statisticians.In this paper, we clarify the interpretation of information-theoretic metrics. In particular, we develop the methods so that their relation to the global properties of probability models is made clear and contrast them with log-linear models for multinomial data. Hopefully, a better understanding of their properties and probabilistic implications will promote their acceptance and correct usage in genetic epidemiology. Our novel development also suggests new approaches to model search and computation.
Tumor Progression Locus 2 (TPL2) Regulates Obesity-Associated Inflammation and Insulin Resistance
Authors: Perfield James W. , Lee Yunkyoung , Shulman Gerald I. , Samuel Varman T. , Jurczak Michael J. , Chang Eugene , Xie Chen , Tsichlis Phillip N. , Obin Martin S. , Greenberg Andrew S. 
Published: February 2011

OBJECTIVE
Obesity-associated low-grade systemic inflammation resulting from increased adipose mass is strongly related to the development of insulin resistance and type 2 diabetes as well as other metabolic complications. Recent studies have demonstrated that the obese metabolic state can be improved by ablating certain inflammatory signaling pathways. Tumor progression locus 2 (TPL2), a kinase that integrates signals from Toll receptors, cytokine receptors, and inhibitor of κ-B kinase-β is an important regulator of inflammatory pathways. We used TPL2 knockout (KO) mice to investigate the role of TPL2 in mediating obesity-associated inflammation and insulin resistance.

RESEARCH DESIGN AND METHODS
Male TPL2KO and wild-type (WT) littermates were fed a low-fat diet or a high-fat diet to investigate the effect of TPL2 deletion on obesity, inflammation, and insulin sensitivity.

RESULTS
We demonstrate that TPL2 deletion does not alter body weight gain or adipose depot weight. However, hyperinsulinemic euglycemic clamp studies revealed improved insulin sensitivity with enhanced glucose uptake in skeletal muscle and increased suppression of hepatic glucose output in obese TPL2KO mice compared with obese WT mice. Consistent with an improved metabolic phenotype, immune cell infiltration and inflammation was attenuated in the adipose tissue of obese TPL2KO mice coincident with reduced hepatic inflammatory gene expression and lipid accumulation.

CONCLUSIONS
Our results provide the first in vivo demonstration that TPL2 ablation attenuates obesity-associated metabolic dysfunction. These data suggest TPL2 is a novel target for improving the metabolic state associated with obesity.
Hyperuricemia as a Mediator of the Proinflammatory Endocrine Imbalance in the Adipose Tissue in a Murine Model of the Metabolic Syndrome
Authors: Baldwin William , McRae Steven , Marek George , Wymer David , Pannu Varinderpal , Baylis Chris , Johnson Richard J. , Sautin Yuri Y. 
Published: February 2011

OBJECTIVE
Hyperuricemia is strongly associated with obesity and metabolic syndrome and can predict visceral obesity and insulin resistance. Previously, we showed that soluble uric acid directly stimulated the redox-dependent proinflammatory signaling in adipocytes. In this study we demonstrate the role of hyperuricemia in the production of key adipokines.

RESEARCH DESIGN AND METHODS
We used mouse 3T3-L1 adipocytes, human primary adipocytes, and a mouse model of metabolic syndrome and hyperuricemia.

RESULTS
Uric acid induced in vitro an increase in the production (mRNA and secreted protein) of monocyte chemotactic protein-1 (MCP-1), an adipokine playing an essential role in inducing the proinflammatory state in adipocytes in obesity. In addition, uric acid caused a decrease in the production of adiponectin, an adipocyte-specific insulin sensitizer and anti-inflammatory agent. Uric acid–induced increase in MCP-1 production was blocked by scavenging superoxide or by inhibiting NADPH oxidase and by stimulating peroxisome-proliferator–activated receptor-γ with rosiglitazone. Downregulation of the adiponectin production was prevented by rosiglitazone but not by antioxidants. In obese mice with metabolic syndrome, we observed hyperuricemia. Lowering uric acid in these mice by inhibiting xanthine oxidoreductase with allopurinol could improve the proinflammatory endocrine imbalance in the adipose tissue by reducing production of MCP-1 and increasing production of adiponectin. In addition, lowering uric acid in obese mice decreased macrophage infiltration in the adipose tissue and reduced insulin resistance.

CONCLUSIONS
Hyperuricemia might be partially responsible for the proinflammatory endocrine imbalance in the adipose tissue, which is an underlying mechanism of the low-grade inflammation and insulin resistance in subjects with the metabolic syndrome.
The finite speed of propagation of solutions of the Neumann problem of a degenerate parabolic equation
Authors: Pan Jiaqing 
Published: February 2011

Abstract
In this paper the finite speed of propagation of solutions and the continuous dependence on the nonlinearity of a degenerate parabolic partial differential equation are discussed. Our objective is to derive an explicit expression for the speed of propagation and the large time behavior of the solution and to show that the solution continuously depends on the nonlinearity of the equation.
Distinct Roles of IL-23 and IL-17 in the Development of Psoriasis-Like Lesions in a Mouse Model
Authors: Nakajima Kimiko , Kanda Takashi , Takaishi Mikiro , Shiga Takeo , Miyoshi Ken , Nakajima Hideki , Kamijima Reiko , Tarutani Masahito , Benson Jacqueline M. , Elloso M. Merle , Gutshall Lester L. , Naso Michael F. , Iwakura Yoichiro , DiGiovanni John , Sano Shigetoshi 
Published: February 2011

Abstract
Psoriasis is an inflammatory disease with dynamic interactions between the immune system and the skin. The IL-23/Th17 axis plays an important role in the pathogenesis of psoriasis, although the exact contributions of IL-23 and IL-17 in vivo remain unclear. K5.Stat3C transgenic mice constitutively express activated Stat3 within keratinocytes, and these animals develop skin lesions with histological and cytokine profiles similar to those of human plaque psoriasis. In this study, we characterized the effects of anti-mouse IL-17A, anti-mouse IL-12/23p40, and anti-mouse IL-23p19 Abs on the development of psoriasis-like lesions in K5.Stat3C transgenic mice. Treatment with anti–IL-12/23p40 or anti–IL-23p19 Abs greatly inhibited 12-O-tetradecanoylphorbol-13-acetate–induced epidermal hyperplasia in the ears of K5.Stat3C mice, whereas the inhibitory effect of an anti–IL-17A Ab was relatively less prominent. Treatment with anti–IL-12/23p40 or anti–IL-23p19 Abs markedly lowered transcript levels of Th17 cytokines (e.g., IL-17 and IL-22), β-defensins, and S100A family members in skin lesions. However, anti–IL-17A Ab treatment did not affect mRNA levels of Th17 cytokines. Crossing IL-17A–deficient mice with K5.Stat3C mice resulted in partial attenuation of 12-O-tetradecanoylphorbol-13-acetate–induced lesions, which were further attenuated by anti–IL-12/23p40 Ab treatment. FACS analysis of skin-draining lymph node cells from mice that were intradermally injected with IL-23 revealed an increase in both IL-22–producing T cells and NK-22 cells. Taken together, this system provides a useful mouse model for psoriasis and demonstrates distinct roles for IL-23 and IL-17.
N-α-Benzoyl-N5-(2-Chloro-1-Iminoethyl)-l-Ornithine Amide, a Protein Arginine Deiminase Inhibitor, Reduces the Severity of Murine Collagen-Induced Arthritis
Authors: Willis Van C. , Gizinski Alison M. , Banda Nirmal K. , Causey Corey P. , Knuckley Bryan , Cordova Kristen N. , Luo Yuan , Levitt Brandt , Glogowska Magdalena , Chandra Piyanka , Kulik Liudmila , Robinson William H. , Arend William P. , Thompson Paul R. , Holers V. Michael 
Published: February 2011

Abstract
Rheumatoid arthritis is associated with the development of autoantibodies to citrullinated self-proteins. Citrullinated synovial proteins, which are generated via the actions of the protein arginine deiminases (PADs), are known to develop in the murine collagen-induced arthritis (CIA) model of inflammatory arthritis. Given these findings, we evaluated whether N-α-benzoyl-N5-(2-chloro-1-iminoethyl)-l-ornithine amide (Cl-amidine), a recently described pan-PAD inhibitor, could affect the development of arthritis and autoimmunity by treating mice in the CIA model with Cl-amidine on days 0–35. Cl-amidine treatment reduced total synovial and serum citrullination, decreased clinical disease activity by ∼50%, and significantly decreased IgG2a anti-mouse type II collagen Abs. Additionally, histopathology scores and total complement C3 deposition were significantly lower in Cl-amidine–treated mice compared with vehicle controls. Synovial microarray analyses demonstrated decreased IgG reactivity to several native and citrullinated epitopes compared with vehicle controls. Cl-amidine treatment had no ameliorative effect on collagen Ab-induced arthritis, suggesting its primary protective mechanism was not mediated through effector pathways. Reduced levels of citrullinated synovial proteins observed in mice treated with Cl-amidine are consistent with the notion that Cl-amidine derives its efficacy from its ability to inhibit the deiminating activity of PADs. In total, these results suggested that PADs are necessary participants in the autoimmune and subsequent inflammatory processes in CIA. Cl-amidine may represent a novel class of disease-modifying agents that modulate aberrant citrullination, and perhaps other immune processes, necessary for the development of inflammatory arthritis.
KLRG1+NKG2A+ CD8 T Cells Mediate Protection and Participate in Memory Responses during γ-Herpesvirus Infection
Authors: Cush Stephanie S. , Flaño Emilio 
Published: February 2011

Abstract
Functional CD8 T cell effector and memory responses are generated and maintained during murine γ-herpesvirus 68 (γHV68) persistent infection despite continuous presentation of viral lytic Ags. However, the identity of the CD8 T cell subpopulations that mediate effective recall responses and that can participate in the generation of protective memory to a γ-herpesvirus infection remains unknown. During γHV68 persistence, ∼75% of γHV68-specific CD8 T cells coexpress the NK receptors killer cell lectin-like receptor G1 (KLRG1) and NKG2A. In this study, we take advantage of this unique phenotype to analyze the capacity of CD8 T cells expressing or not expressing KLRG1 and NKG2A to mediate effector and memory responses. Our results show that γHV68-specific KLRG1+NKG2A+ CD8 T cells have an effector memory phenotype as well as characteristics of polyfunctional effector cells such us IFN-γ and TNF-α production, killing capacity, and are more efficient at protecting against a γHV68 challenge than their NKG2A−KLRG1− counterparts. Nevertheless, γHV68-specific NKG2A+KLRG1+ CD8 T cells express IL-7 and IL-15 receptors, can survive long-term without cognate Ag, and subsequently mount a protective response during antigenic recall. These results highlight the plasticity of the immune system to generate protective effector and proliferative memory responses during virus persistence from a pool of KLRG1+NKG2A+ effector memory CD8 T cells.
IL-9 Promotes Th17 Cell Migration into the Central Nervous System via CC Chemokine Ligand-20 Produced by Astrocytes
Authors: Zhou Yan , Sonobe Yoshifumi , Akahori Tomohiko , Jin Shijie , Kawanokuchi Jun , Noda Mariko , Iwakura Yoichiro , Mizuno Tetsuya , Suzumura Akio 
Published: February 2011

Abstract
Newly discovered IL-9–producing helper T cells (Th9) reportedly exert both aggravating and suppressive roles on experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. However, it is still unclear whether Th9 is a distinct Th cell subset and how IL-9 functions in the CNS. In this study, we show that IL-9 is produced by naive CD4+ T cells that were stimulated with anti-CD3 and anti-CD28 Abs under the conditions of Th2-, inducible regulatory T cell-, Th17-, and Th9-polarizing conditions and that IL-9 production is significantly suppressed in the absence of IL-4, suggesting that IL-4 is critical for the induction of IL-9 by each producing cell. The IL-9 receptor complex, IL-9R and IL-2Rγ, is constitutively expressed on astrocytes. IL-9 induces astrocytes to produce CCL-20 but not other chemokines, including CCL-2, CCL-3, and CXCL-2 by astrocytes. The conditioned medium of IL-9–stimulated astrocytes induces Th17 cell migration in vitro, which is cancelled by adding anti–CCL-20 neutralizing Abs. Treating with anti–IL-9 neutralizing Abs attenuates experimental autoimmune encephalomyelitis, decreases the number of infiltrating Th17 cells, and reduces CCL-20 expression in astrocytes. These results suggest that IL-9 is produced by several Th cell subsets in the presence of IL-4 and induces CCL-20 production by astrocytes to induce the migration of Th17 cells into the CNS.
Interplay between TNF and Regulatory T Cells in a TNF-Driven Murine Model of Arthritis
Authors: Biton Jérôme , Semerano Luca , Delavallée Laure , Lemeiter Delphine , Laborie Marion , Grouard-Vogel Géraldine , Boissier Marie-Christophe , Bessis Natacha 
Published: February 2011

Abstract
CD4+CD25+Foxp3+ regulatory T cells (Treg) are involved in several autoimmune diseases, including rheumatoid arthritis. TNF-α blockers induce therapeutic benefits in rheumatoid arthritis via a variety of mechanisms. We aimed to characterize the impact on Treg of TNF-α overexpression in vivo and of TNF-α inhibiting treatments. We used human TNF-α transgenic mice as a model of strictly TNF-α–dependent arthritis. Our study showed that initial Treg frequency was lower in TNF-α transgenic mice than in wild-type mice. However, the course of arthritis was marked by elevation of Treg frequency and a dramatic increase in expression of TNFR2. Antagonizing TNF-α with either the anti-human TNF-α Ab (infliximab) or active immunotherapy (TNF-kinoid) increased the Treg frequency and upregulated CTLA-4, leading to enhancement of suppressor activity. Moreover, both anti–TNF-α strategies promoted the differentiation of a CD62L− Treg population. In conclusion, in an in vivo model of TNF-α–driven arthritis, Treg frequency increased with inflammation but failed to control the inflammatory process. Both passive and active TNF-α–inhibiting strategies restored the suppressor activity of Treg and induced the differentiation of a CD62L− Treg population.
Plasma amino acid concentrations and mRNA expression of components related to protein degradation in lambs with nutritionally induced metabolic acidosis
Authors: Greenwood S.L. , AlZahal O. , Purdie N.G. , Swanson K.C. , McBride B.W. 
Published: February 2011

Aspects of amino acid metabolism and proteolysis were examined in lambs with metabolic acidosis. Lambs (n = 30; 42.8 ± 4.1 kg BW) were randomly assigned to treatment groups, receiving a topdress of either (1) dried distiller’s grain (DDG; anion load of 7 mEq 100 g-1 DM, (2) DDG + NH4Cl-treated DDG (anionic load of -29 mEq 100 g-1 DM), or (3) DDG + NH4Cl-treated DDG (anionic load of -42 mEq 100 g-1 DM). Lambs were maintained on DDG topdress for 9 d, after which increasing amounts of DDG were substituted with NH4Cl-treated DDG in the treatment group diets from day 10 to day 21. Blood gas, blood acid-base, urine pH and plasma amino acid concentrations were determined on day 9 and day 21. On day 22, lambs were slaughtered and kidney, liver, extensor digitorum longus muscle (EDL), and soleus muscle samples were collected. Blood pH, bicarbonate, base excess of blood and extracellular fluid, total CO2 and urinary pH were linearly decreased as dietary anionic load increased (P < 0.001). Plasma glutamine, glycine, histidine, arginine and asparagine increased linearly (P < 0.06) due to acidosis, while renal glutamate dehydrogenase (P = 0.02) and hepatic glutamine synthetase (P = 0.02) mRNA expression were linearly increased. Caspase-3 mRNA expression was linearly decreased in soleus muscle by acidosis (P = 0.01), but not in EDL muscle. No change in mRNA expression of components of the ubiquitin-mediated proteolytic pathway was observed in either muscle. These results suggest muscle-specific regulation of caspase-3 mRNA expression during metabolic acidosis in sheep.
Free endotoxins in the feces of lactating dairy cows
Authors: Li S. , Khafipour E. , Krause D.O. , Rodriguez-Lecompte J.C. , Plaizier J.C. 
Published: February 2011

A survey was conducted on 300 lactating dairy cows on 10 dairy farms to determine how risk factors for and symptoms of excessive grain feeding and subacute ruminal acidosis are associated with the concentrations of endotoxins in feces measured with the Limulus amoebocyte lysate test. Increases in days in milk and haptoglobin in blood plasma were associated with lower (P = 0.02) and higher (P = 0.02) fecal endotoxin, respectively. The five farms with a dietary neutral detergent fibre (NDF) content higher than 33.8% of DM had lower (P < 0.01) fecal endotoxin than those with a dietary NDF content lower than 33.8% of DM (31 790 vs. 69 276 endotoxin units (EU) g-1 of wet feces, P < 0.01). Parity, milk yield, milk fat percentage, milk protein percentage, the blood plasma concentration of serum amyloid A, and the dietary content of physically effective fibre were not associated with the fecal endotoxin concentration.
Effects of extra feeding in mid-pregnancy for three successive parities on lean sows’ productive performance and longevity
Authors: Cerisuelo A. , Sala R. , Gasa J. , Carrión D. , Coma J. , Chapinal N. , Baucells M.D. 
Published: February 2011

The aim of this study was to investigate the long-term effects of increasing feeding allowance during mid-pregnancy in sows. A total of 103 PIC pregnant sows (mixed parity) were allocated to two treatments: control (C, n = 49) were fed 2.5-3.0 kg d-1 (12.1 MJ ME kg-1) and extra-fed (E, n = 54) received +2.0 kg d-1 of the same feed from day 45 to 85 of gestation over three consecutive cycles. Body weight, backfat thickness (BF) and loin depth were measured on days 45 and 85 of gestation, farrowing and weaning. Litter and sows performance were recorded during lactation and post-weaning. Overall culling rates were 61 and 67% for C and E groups, respectively. After three cycles, E sows showed a positive BF balance in contrast to C sows (E = +1.46 mm and C= -1.81 mm, P < 0.05). In cycle 3, E sows presented greater piglet birth weights than C sows, being mainly evident in sows that were nulliparous at the onset of the experiment (P < 0.05). Extra-fed sows showed a greater incidence of mastitis-metritis-agalactia syndrome than C sows (P = 0.003). Thus, increasing feeding allowance during mid-pregnancy positively affected BF balance and birth weight in nulliparous, but impaired the sows’ ability to produce milk in the long-term.