bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multifactorial T-cell Hypofunction That Is Reversible Can Limit the Efficacy of Chimeric Antigen Receptor–Transduced Human T cells in Solid Tumors
Authors: Moon Edmund K. , Wang Liang-Chuan , Dolfi Douglas V. , Wilson Caleph B. , Ranganathan Raghuveer , Sun Jing , Kapoor Veena , Scholler John , Puré Ellen , Milone Michael C. , June Carl H. , Riley James L. , Wherry E. John , Albelda Steven M. 
Published: June 2014

Abstract
Purpose: Immunotherapy using vaccines or adoptively transferred tumor-infiltrating lymphocytes (TIL) is limited by T-cell functional inactivation within the solid tumor microenvironment. The purpose of this study was to determine whether a similar tumor-induced inhibition occurred with genetically modified cytotoxic T cells expressing chimeric antigen receptors (CAR) targeting tumor-associated antigens.
Experimental Design: Human T cells expressing CAR targeting mesothelin or fibroblast activation protein and containing CD3ζ and 4–1BB cytoplasmic domains were intravenously injected into immunodeficient mice bearing large, established human mesothelin-expressing flank tumors. CAR TILs were isolated from tumors at various time points and evaluated for effector functions and status of inhibitory pathways.
Results: CAR T cells were able to traffic into tumors with varying efficiency and proliferate. They were able to slow tumor growth, but did not cause regressions or cures. The CAR TILs underwent rapid loss of functional activity that limited their therapeutic efficacy. This hypofunction was reversible when the T cells were isolated away from the tumor. The cause of the hypofunction seemed to be multifactorial and was associated with upregulation of intrinsic T-cell inhibitory enzymes (diacylglycerol kinase and SHP-1) and the expression of surface inhibitory receptors (PD1, LAG3, TIM3, and 2B4).
Conclusions: Advanced-generation human CAR T cells are reversibly inactivated within the solid tumor microenvironment of some tumors by multiple mechanisms. The model described here will be an important tool for testing T cell–based strategies or systemic approaches to overcome this tumor-induced inhibition. Our results suggest that PD1 pathway antagonism may augment human CAR T-cell function. Clin Cancer Res; 20(16); 4262–73. ©2014 AACR.
Skin Barrier Dysfunction and Low Antimicrobial Peptide Expression in Cutaneous T-cell Lymphoma
Authors: Suga Hiraku , Sugaya Makoto , Miyagaki Tomomitsu , Ohmatsu Hanako , Kawaguchi Makiko , Takahashi Naomi , Fujita Hideki , Asano Yoshihide , Tada Yayoi , Kadono Takafumi , Sato Shinichi 
Published: June 2014

AbstractPurpose: Atopic dermatitis is characterized by decreased expression of filaggrin and loricrin. Patients with atopic dermatitis often suffer from skin infections, which are also frequently seen in patients with cutaneous T-cell lymphoma (CTCL). In this study, we aimed to investigate the skin barrier in CTCL.Experimental Design: We assessed skin moisture and transepidermal water loss (TEWL) in patients with CTCL. We next examined mRNA expression levels of filaggrin, loricrin, and antimicrobial peptides (AMP) in skin samples of CTCL, using skin from healthy volunteers and patients with atopic dermatitis or psoriasis as controls. Immunostainings for filaggrin, loricrin, and S100 proteins were also performed.Results: Lower levels of skin moisture accompanied by higher levels of TEWL were seen in lesional skin of CTCL than in normal skin. CTCL lesional skin contained lower levels of filaggrin and loricrin mRNA than normal skin, which was also true with atopic dermatitis and psoriatic skin. mRNA expression levels of filaggrin in CTCL skin negatively correlated with disease severity markers. Expression levels of AMPs in lesional skin of CTCL and atopic dermatitis were significantly lower than in psoriatic skin. Immunohistochemistry confirmed decreased expression of filaggrin and loricrin in CTCL, atopic dermatitis, and psoriatic skin and enhanced expression of S100 proteins in psoriatic skin.Conclusions: Our results show that there is barrier dysfunction in CTCL skin, similar to what is seen with atopic dermatitis skin. In addition, low AMP expression in CTCL skin was documented when compared with psoriatic skin, which may explain frequent infections that can occur in patients with CTCL. Clin Cancer Res; 20(16); 4339–48. ©2014 AACR.
Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients
Authors: Damm Frederik , Mylonas Elena , Cosson Adrien , Yoshida Kenichi , Della Valle Véronique , Mouly Enguerran , Diop M'boyba , Scourzic Laurianne , Shiraishi Yuichi , Chiba Kenichi , Tanaka Hiroko , Miyano Satoru , Kikushige Yoshikane , Davi Frederick , Lambert Jérôme , Gautheret Daniel , Merle-Béral Hélène , Sutton Laurent , Dessen Philippe , Solary Eric , Akashi Koichi , Vainchenker William , Mercher Thomas , Droin Nathalie , Ogawa Seishi , Nguyen-Khac Florence , Bernard Olivier A. 
Published: June 2014

AbstractAppropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase.Significance: The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL. Cancer Discov; 4(9); 1088–1101. ©2014 AACR.See related commentary by Jiang and Elemento, p. 995This article is highlighted in the In This Issue feature, p. 973
Rituximab for treatment of inhibitors in haemophilia A
Authors: Leissinger Cindy , Josephson Cassandra , Konkle Barbara , Kruse-Jarres Rebecca , Ragni Margaret , Journeycake Janna , Valentino Leonard , Key Nigel , Gill Joan , McCrae Keith , Neufeld Ellis , Manno Catherine , Raffini Leslie , Saxena Kapil , Torres Marcela , Marder Victor , Bennett Carolyn , Assmann Susan , Granger Suzanne 
Published: June 2014

SummaryThe development of antibodies against infused factor VIII (FVIII) in patients with haemophilia A is a serious complication leading to poorly controlled bleeding and increased morbidity. No treatment has been proven to reduce high titre antibodies in patients who fail immune tolerance induction or are not candidates for it. The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) study was a phase II trial to assess whether rituximab can reduce anamnestic FVIII antibody (inhibitor) titres. Male subjects with severe congenital haemophilia A and an inhibitor titre ≥5 Bethesda Units/ml (BU) following a FVIII challenge infusion received rituximab 375 mg/m2 weekly for weeks 1 through 4. Post-rituximab inhibitor titres were measured monthly from week 6 through week 22 to assess treatment response. Of 16 subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to <5 BU, persisting after FVIII re-challenge. One subject had a minor response, defined as a fall in inhibitor titre to <5 BU, increasing to 5–10 BU after FVIII re-challenge, but <50% of the original peak inhibitor titre. Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies.Trial: “Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A: The RICH Study. Registered as Clinical Trials.gov identifier- NCT00331006.
O mito da renovabilidade na expansão da agroindústria sucroenergética
Authors: Xavier Carlos Vinicius , Santos Luiz Henrique de Melo dos 
Published: June 2014

No contexto da expansão da agroindústria sucroenergética, verifica-se um esforço do setor por relacionar a temática ambiental às atividades por este desenvolvidas, em especial à produção do etanol. Observa-se a conformação de um discurso que prima pela identificação do processo de geração do agrocombustível enquanto uma forma renovável de produção energética. Em contraposição aos argumentos que ressaltam tal renovabilidade, ou mesmo que identifica no etanol de cana-de-açúcar a existência de uma suposta fonte de energia limpa, propõe-se neste artigo desenvolver uma análise que revela tal discurso enquanto um mito. Baseando-se em uma reflexão interdisciplinar, discutimos, portanto, alguns dos impactos territoriais resultantes da atual cadeia produtiva do etanol.
Expansão canavieira e impactos sócio-espaciais da produção de agrocombustível no Triângulo Mineiro (1980-2012)
Authors: Campos Natália Lorena , Cleps Junior João 
Published: June 2014

O tema da pesquisa envolve a produção de agrocombustíveis e a expansão da produção canavieira na região do Triângulo Mineiro/Alto Paranaíba, que é uma das principais discussões da questão agrária atual, a partir do agravamento de problemas no campo, como a incorporação de terras para a monocultura canavieira. Como principais objetivos do trabalho, buscamos compreender as dimensões socioterritoriais da expansão da produção canavieira recente para a produção de agrocombustíveis no espaço agrário de Minas Gerais e suas relações com as estruturas sociais rurais (principalmente a produção camponesa/familiar); analisar o desenvolvimento da agroindústria canavieira frente as demais produções agrícolas e pecuária da região e verificar os principais impactos da expansão dessa monocultura. Com isso, foi realizado uma revisão bibliográfica da temática afim e levantamento de dados e informações em fontes secundárias. Nesse sentido, temos a apropriação dos territórios para a produção canavieira como a principal causa dos conflitos e disputas territoriais no campo brasileiro, onde a industrialização da agricultura subordina a natureza ao capital.
Fibroblast Growth Factor-23 and Incident Atrial Fibrillation
Authors: Mathew Jehu S. , Sachs Michael C. , Katz Ronit , Patton Kristen K. , Heckbert Susan R. , Hoofnagle Andrew N. , Alonso Alvaro , Chonchol Michel , Deo Rajat , Ix Joachim H. , Siscovick David S. , Kestenbaum Bryan , de Boer Ian H. 
Published: June 2014

Background—
Fibroblast growth factor-23 (FGF-23) is a hormone that promotes urinary phosphate excretion and regulates vitamin D metabolism. Circulating FGF-23 concentrations increase markedly in chronic kidney disease and are associated with increased risk of clinical cardiovascular events. FGF-23 may promote atrial fibrillation (AF) by inducing left ventricular hypertrophy and diastolic and left atrial dysfunction.

Methods and Results—

We tested the associations of circulating FGF-23 concentration with incident AF among 6398 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 1350 participants in the Cardiovascular Health Study (CHS), all free of clinical cardiovascular disease at baseline. Over a median of 7.7 and 8.0 years of follow-up, we observed 291 and 229 incident AF events in MESA and CHS, respectively. In multivariable Cox proportional hazards models, each 2-fold-higher FGF-23 concentration was associated with a 41% higher risk of incident AF in MESA (hazard ratio, 1.41; 95% confidence interval, 1.13–1.76;
P
=0.003) and a 30% higher risk of incident AF in CHS (hazard ratio, 1.30; 95% confidence interval, 1.05–1.61;
P
=0.016) after adjustment for potential confounding characteristics, including kidney disease. Serum phosphate concentration was significantly associated with incident AF in MESA (hazard ratio, 1.15 per 0.5 mg/dL; 95% confidence interval, 1.02–1.31;
P
=0.023) but not CHS. In MESA, an association of low estimated glomerular filtration rate with incident AF was partially attenuated by adjustment for FGF-23.

Conclusion—
Higher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.
Regional Model Simulations of the 2008 Drought in Southern South America Using a Consistent Set of Land Surface Properties
Authors: Müller Omar V. , Berbery Ernesto Hugo , Alcaraz-Segura Domingo , Ek Michael B. 
Published: June 2014

AbstractThis work discusses the land surface–atmosphere interactions during the severe drought of 2008 in southern South America, which was among the most severe in the last 50 years in terms of both intensity and extent. Once precipitation returned to normal values, it took about two months for the soil moisture content and vegetation to recover. The land surface effects were examined by contrasting long-term simulations using a consistent set of satellite-derived annually varying land surface biophysical properties against simulations using the conventional land-cover types in the Weather Research and Forecasting Model–Noah land surface model (WRF–Noah). The new land-cover dataset is based on ecosystem functional properties that capture changes in vegetation status due to climate anomalies and land-use changes.The results show that the use of realistic information of vegetation states enhances the model performance, reducing the precipitation biases over the drought region and over areas of excessive precipitation. The precipitation bias reductions are attributed to the corresponding changes in greenness fraction, leaf area index, stomatal resistance, and surface roughness. The temperature simulation shows a generalized increase, which is attributable to a lower vegetation greenness and a doubling of the stomatal resistance that reduces the evapotranspiration rate. The increase of temperature has a beneficial effect toward the eastern part of the domain with a notable reduction of the bias, but not over the central region where the bias is increased. The overall results suggest that an improved representation of the surface processes may contribute to improving the predictive skill of the model system.
A Study of the Role of Daytime Land–Atmosphere Interactions on Nocturnal Convective Activity in the Southern Great Plains during CLASIC
Authors: Erlingis Jessica M. , Barros Ana P. 
Published: June 2014

AbstractThis study examines whether and how land–atmosphere interactions can have an impact on nocturnal convection over the southern Great Plains (SGP) through numerical simulations of an intense nocturnal mesoscale convective system (MCS) on 19–20 June 2007 with the Weather Research and Forecasting (WRF) Model. High-resolution nested simulations were conducted using realistic and idealized land surfaces and two planetary boundary layer (PBL) parameterizations (PBLp): Yonsei University (YSU) and Mellor–Yamada–Janjić (MYJ). Differences in timing and amount of MCS precipitation among observations and model results were examined in the light of daytime land–atmosphere interactions, nocturnal prestorm environment, and cold pool strength. At the meso-γ scale, land cover and soil type have as much of an effect on the simulated prestorm environment as the choice of PBLp: MYJ simulations exhibit strong sensitivity to changes in the land surface in contrast to negligible impact in the case of YSU. At the end of the afternoon, as the boundary layer collapses, a more homogeneous and deeper PBL (and stronger low-level shear) is evident for YSU as compared to MYJ when initial conditions and land surface properties are the same. At the meso-β scale, propagation speed is faster and organization (bow echo morphology) and cold pool strength are enhanced when nocturnal PBL heights are higher, and there is stronger low-level shear in the prestorm environment independent of the boundary layer parameterization for different land surface conditions. A comparison of one- and two-way nested MYJ results demonstrates how daytime land–atmosphere interactions modify the prestorm environment remotely through advection of low-level thermodynamic features. This remote feedback strongly impacts the MCS development phase as well as its spatial organization and propagation velocity and, consequently, nocturnal rainfall. These results indicate that synoptic- and meso-α-scale dynamics can play an important role in determining the spatial and temporal scales over which precipitation feedbacks of land–atmosphere interactions emerge regionally. Finally, this study demonstrates the high degree of uncertainty in defining the spatial and temporal scales of land–atmosphere interactions where and when organized convection is dominant.
Effects of acute alcohol consumption and processing of emotion in faces: Implications for understanding alcohol-related aggression
Authors: Attwood Angela S , Munafò Marcus R 
Published: June 2014

The negative consequences of chronic alcohol abuse are well known, but heavy episodic consumption (“binge drinking”) is also associated with significant personal and societal harms. Aggressive tendencies are increased after alcohol but the mechanisms underlying these changes are not fully understood. While effects on behavioural control are likely to be important, other effects may be involved given the widespread action of alcohol. Altered processing of social signals is associated with changes in social behaviours, including aggression, but until recently there has been little research investigating the effects of acute alcohol consumption on these outcomes. Recent work investigating the effects of acute alcohol on emotional face processing has suggested reduced sensitivity to submissive signals (sad faces) and increased perceptual bias towards provocative signals (angry faces) after alcohol consumption, which may play a role in alcohol-related aggression. Here we discuss a putative mechanism that may explain how alcohol consumption influences emotional processing and subsequent aggressive responding, via disruption of orbitofrontal cortex (OFC)-amygdala connectivity. While the importance of emotional processing on social behaviours is well established, research into acute alcohol consumption and emotional processing is still in its infancy. Further research is needed and we outline a research agenda to address gaps in the literature.
Few older people in New Zealand who commit suicide receive specialist psychogeriatric services
Authors: Cheung Gary , Casey Jane 
Published: June 2014

Objective: Suicide in older people is a growing public health concern in many parts of the world. The literature on this issue is lacking in New Zealand. The aim of this study is to ascertain whether this group is accessing specialist psychogeriatric services. A retrospective case series study of completed suicides in older people (≥65 years) during a three-year period from January 2010 to December 2012 was performed. Method: An online survey detailing demographic and clinical information was completed by psychiatrists in 15 of the 20 District Health Boards in New Zealand. Results: Only about 15% of older people who committed suicide were accessing specialist psychogeriatric services and the group with the highest suicide rate (men≥85 years) did not feature in specialist services. Depression (61%) was the most common diagnosis and nearly half (35%) had had contact with specialist services within three days prior to the suicide. Over half (52%) had a history of past suicide attempt(s). Conclusions: Older people who complete suicide are infrequently accessing specialist services. In those that do, there are questions to be answered regarding suicide prediction and prevention for this high-risk group of vulnerable individuals. More research is required targeting those not accessing specialist services, in particular the high risk group of older men. The role of general practitioner, community care, the assessment and management of depression and whether there is any access issue to specialist psychogeriatric services require elucidation.
The influence of personal communities on the self-management of medication taking: A wider exploration of medicine work
Authors: Cheraghi-Sohi Sudeh , Jeffries Mark , Stevenson Fiona , Ashcroft Darren M , Carr Matthew , Oliver Kathryn , Rogers Anne 
Published: June 2014

Objectives There is a lack of focus on the broader social context, networks and influences on medicine-taking as part of illness work. This work adopts a social network approach and seeks to explicate the nature of medicine-taking work that people with multiple long-term conditions (LTCs) and their social network members (SNMs) do in attempting to take their medications on a daily basis, the division of labour amongst these members and when and why SNMs become involved in that work. Methods Semi-structured interviews were conducted with 20 people who had multiple LTCs. Medication networks were constructed and the division of labour in relation to medication-work was explored. Results Four types of medication-work emerged: medication articulation, surveillance, emotional and informational. Involvement of SNMs in medication-work was selective, performed primarily by family members, within the home. Involvement reflected network composition and/or an individual’s conceptualisation/presentation of self. Discussion Our findings support and extend the conceptualisation of routine medicine-taking as a type of work. Furthermore, we illustrate the involvement of SNMs in aspects of medicine-work. Health professionals should explore and support the role of SNMs in medicine-taking where possible. Future research should explore the implications of network types and compositions on medicine-taking and associated work.