bluuebunny/crossref_metadata_2025_split huggingface dataset:
Indications for cobalamin level assessment in departments of internal medicine: a prospective practice survey
Authors: Chiche Laurent , Mancini Julien , Arlet Jean-Benoît ,   BDOSE study investigators, Bernard Fanny , Bernard Sylvain , Carassou Philippe , Chaigne Benjamin , Chaussade Hélène , Cinquetti Gaël , Contentin Laetitia , Deboysson Hubert , Ebbo Mikaël , Géri Guillaume , Graveleau Julie , Jamilloux Yvan , Karkowski Ludovic , Inghilleri Marie-Laure , Lioget Bertrand , Lhommet Claire , Mourot Rachel , Nielsen Louise , Pasquet Florian , Peigne Vincent , Puyade Mathieu , Roux Xavier , Saadi Samir , Savini Hélène , Weitten Thierry 
Published: May 2013

Abstract

Background
Cobalamin (Cb) blood levels are frequently measured among inpatients, but the relevance of Cb determination has not been correctly assessed in this clinical setting.

Purpose
We aimed to prospectively evaluate current indications compared to traditional guidelines for assessing Cb blood levels among inpatients from internal medicine departments.

Study design
This study was conducted in French departments of internal medicine between 2008 and 2009. Inpatients who underwent Cb blood level determination during a 6-week study period were eligible.

Results
380 consecutive adult patients were included. The three most common indications for Cb assessment were anaemia (62.6%), cognitive impairment (20.2%) and undernutrition (17.4%). Traditional indications (ie, macrocytic non-regenerative anaemia, isolated macrocytosis, dementia and proprioceptive disorders) accounted for only 33.9% of all tests. Cb deficiency was identified in 40 (10.5%) of the 380 patients tested. Overall, traditional indications were not associated with a significantly higher prevalence of patients with low Cb levels than current guidelines (14% vs 8.8%; p=0.119). Non-regenerative macrocytic anaemia was the only indication with a significantly better performance compared to all other indications (11 of 62 patients (17.7%) vs 29 of 318 patients (9.1%); OR 2.15 (1.01−4.57), p=0.047). The main aetiological causes of Cb deficiency were intake deficiency, pernicious anaemia and food-Cb malabsorption. Homocysteine or methylmalonic acid dosage testing was very rarely performed.

Conclusions
Traditional indications did not perform better than other indications observed in current practice for identifying low Cb levels among inpatients from internal medicine departments. Future studies are needed to establish robust guidelines for inpatient screening.
Avirulent Toxoplasma gondii Generates Therapeutic Antitumor Immunity by Reversing Immunosuppression in the Ovarian Cancer Microenvironment
Authors: Baird Jason R. , Fox Barbara A. , Sanders Kiah L. , Lizotte Patrick H. , Cubillos-Ruiz Juan R. , Scarlett Uciane K. , Rutkowski Melanie R. , Conejo-Garcia Jose R. , Fiering Steven , Bzik David J. 
Published: May 2013

Abstract
Reversing tumor-associated immunosuppression seems necessary to stimulate effective therapeutic immunity against lethal epithelial tumors. Here, we show this goal can be addressed using cps, an avirulent, nonreplicating uracil auxotroph strain of the parasite Toxoplasma gondii (T. gondii), which preferentially invades immunosuppressive CD11c+ antigen-presenting cells in the ovarian carcinoma microenvironment. Tumor-associated CD11c+ cells invaded by cps were converted to immunostimulatory phenotypes, which expressed increased levels of the T-cell receptor costimulatory molecules CD80 and CD86. In response to cps treatment of the immunosuppressive ovarian tumor environment, CD11c+ cells regained the ability to efficiently cross-present antigen and prime CD8+ T-cell responses. Correspondingly, cps treatment markedly increased tumor antigen-specific responses by CD8+ T cells. Adoptive transfer experiments showed that these antitumor T-cell responses were effective in suppressing solid tumor development. Indeed, intraperitoneal cps treatment triggered rejection of established ID8-VegfA tumors, an aggressive xenograft model of ovarian carcinoma, also conferring a survival benefit in a related aggressive model (ID8-Defb29/Vegf-A). The therapeutic benefit of cps treatment relied on expression of IL-12, but it was unexpectedly independent of MyD88 signaling as well as immune experience with T. gondii. Taken together, our results establish that cps preferentially invades tumor-associated antigen-presenting cells and restores their ability to trigger potent antitumor CD8+ T-cell responses. Immunochemotherapeutic applications of cps might be broadly useful to reawaken natural immunity in the highly immunosuppressive microenvironment of most solid tumors. Cancer Res; 73(13); 3842–51. ©2013 AACR.
Genomic Profiling Defines Subtypes of Prostate Cancer with the Potential for Therapeutic Stratification
Authors: Schoenborn Jamie R. , Nelson Pete , Fang Min 
Published: May 2013

Abstract
The remarkable variation in prostate cancer clinical behavior represents an opportunity to identify and understand molecular features that can be used to stratify patients into clinical subgroups for more precise outcome prediction and treatment selection. Significant progress has been made in recent years in establishing the composition of genomic and epigenetic alterations in localized and advanced prostate cancers using array-based technologies and next-generation sequencing approaches. The results of these efforts shed new light on our understanding of this disease and point to subclasses of prostate cancer that exhibit distinct vulnerabilities to therapeutics. The goal of this review is to categorize the genomic data and, where available, corresponding expression, functional, or related therapeutic information, from recent large-scale and in-depth studies that show a new appreciation for the molecular complexity of this disease. We focus on how these results inform our growing understanding of the mechanisms that promote genetic instability, as well as routes by which specific genes and biologic pathways may serve as biomarkers or potential targets for new therapies. We summarize data that indicate the presence of genetic subgroups of prostate cancers and show the high level of intra- and intertumoral heterogeneity, as well as updated information on disseminated and circulating tumor cells. The integrated analysis of all types of genetic alterations that culminate in altering critical biologic pathways may serve as the impetus for developing new therapeutics, repurposing agents used currently for treating other malignancies, and stratifying early and advanced prostate cancers for appropriate interventions. Clin Cancer Res; 19(15); 4058–66. ©2013 AACR.
Stearoyl Co-A Desaturase 1 as a ccRCC Therapeutic Target: Death by Stress
Authors: Leung Janet Y. , Kim William Y. 
Published: May 2013

Abstract
There is a need for the discovery of novel therapeutic strategies to effectively treat advanced clear cell renal cell carcinoma (ccRCC). Inhibition of stearoyl-coA desaturase 1 (SCD1) in ccRCC reveals antitumor activity, independently and in synergy with mTOR inhibition. SCD1 may be a potential novel therapeutic target in treating ccRCC. Clin Cancer Res; 19(12); 3111–3. ©2013 AACR.
Novel Curcumin-Loaded Magnetic Nanoparticles for Pancreatic Cancer Treatment
Authors: Yallapu Murali M. , Ebeling Mara C. , Khan Sheema , Sundram Vasudha , Chauhan Neeraj , Gupta Brij K. , Puumala Susan E. , Jaggi Meena , Chauhan Subhash C. 
Published: May 2013

Abstract
Curcumin (CUR), a naturally occurring polyphenol derived from the root of Curcuma longa, has showed potent anticancer and cancer prevention activity in a variety of cancers. However, the clinical translation of CUR has been significantly hampered due to its extensive degradation, suboptimal pharmacokinetics, and poor bioavailability. To address these clinically relevant issues, we have developed a novel CUR-loaded magnetic nanoparticle (MNP-CUR) formulation. Herein, we have evaluated the in vitro and in vivo therapeutic efficacy of this novel MNP-CUR formulation in pancreatic cancer. Human pancreatic cancer cells (HPAF-II and Panc-1) exhibited efficient internalization of the MNP-CUR formulation in a dose-dependent manner. As a result, the MNP-CUR formulation effectively inhibited growth of HPAF-II and Panc-1 cells in cell proliferation and colony formation assays. The MNP-CUR formulation suppressed pancreatic tumor growth in an HPAF-II xenograft mouse model and improved the survival of mice by delaying tumor growth. The growth-inhibitory effect of MNP-CUR formulation correlated with the suppression of proliferating cell nuclear antigen (PCNA), B-cell lymphoma-extra large (Bcl-xL), induced myeloid leukemia cell differentiation protein (Mcl-1), cell surface–associated Mucin 1 (MUC1), collagen I, and enhanced membrane β-catenin expression. MNP-CUR formulation did not show any sign of hemotoxicity and was stable after incubation with human serum proteins. In addition, the MNP-CUR formulation improved serum bioavailability of CUR in mice up to 2.5-fold as compared with free CUR. Biodistribution studies show that a significant amount of MNP-CUR formulation was able to reach the pancreatic xenograft tumor(s), which suggests its clinical translational potential. In conclusion, this study suggests that our novel MNP-CUR formulation can be valuable for the treatment of pancreatic cancer. Mol Cancer Ther; 12(8); 1471–80. ©2013 AACR.
In vivo platelet activation and platelet hyperreactivity in abacavir-treated HIV-infected patients
Authors: Belfiori Barbara , Petito Eleonora , Guglielmini Giuseppe , Malincarne Lisa , Mezzasoma AnnaMaria , Sebastiano Manuela , Conti Valentina , Giannini Silvia , Bonora Stefano , Baldelli Franco , Falcinelli Emanuela , Francisci Daniela , Gresele Paolo 
Published: May 2013

SummaryAbacavir (ABC) has been associated with ischaemic cardiovascular events in HIV-infected patients, but the pathogenic mechanisms are unknown. Aim of our study was to assess whether ABC induces in vivo platelet activation and ex vivo platelet hyper-reactivity. In a retrospective, case-control study, in vivo platelet activation markers were measured in 69 HIV-infected patients, before starting therapy and after 6–12 months of either ABC (n=35) or tenofovir (TDF) (n=34), and compared with those from 20 untreated HIV-infected patients. A subgroup of patients was restudied after 28–34 months for ex vivo platelet reactivity. In vivo platelet activation markers were assessed by ELISA or flow cytometry, ex vivo platelet reactivity by light transmission aggregometry (LTA) and PFA-100®. The in vitro effects of the ABC metabolite, carbovir triphosphate, on aggregation and intra-platelet cGMP were also studied. sPLA2, sPsel and sGPV increased significantly 6–12 months after the beginning of ABC, but not of TDF or of no treatment. Ex vivo platelet function studies showed enhanced LTA, shorter PFA-100® C/ADP closure time and enhanced platelet expression of P-sel and CD40L in the ABC group. The intake of ABC blunted the increase of intraplatelet cGMP induced by nitric oxide (NO) and acutely enhanced collagen-induced aggregation. Preincubation of control platelets with carbovir triphosphate in vitro enhanced platelet aggregation and blunted NO-induced cGMP elevation. In conclusion, treatment with ABC enhances in vivo platelet activation and induces platelet hyperreactivity by blunting the inhibitory effects of NO on platelets. These effects may lead to an increase of ischaemic cardiovascular events.
Identification and characterisation of mutations associated with von Willebrand disease in a Turkish patient cohort
Authors: Abuzenadah Adel , Cartwright Ashley , Al-Shammari Nawal , Coyle Rachael , Eckert Michaela , Al-Buhairan Ahlam , Messenger Sarah , Budde Ulrich , Gürsel Türkiz , Ingerslev Jørgen , Peake Ian , Goodeve Anne , Hampshire Daniel 
Published: May 2013

SummarySeveral cohort studies have investigated the molecular basis of von Willebrand disease (VWD); however, these have mostly focused on European and North American populations. This study aimed to investigate mutation spectrum in 26 index cases (IC) from Turkey diagnosed with all three VWD types, the majority (73%) with parents who were knowingly related. IC were screened for mutations using multiplex ligation-dependent probe amplification and analysis of all von Willebrand factor gene (VWF) exons and exon/intron boundaries. Selected missense mutations were expressed in vitro. Candidate VWF mutations were identified in 25 of 26 IC and included propeptide missense mutations in four IC (two resulting in type 1 and two in recessive 2A), all influencing VWF expression in vitro. Four missense mutations, a nonsense mutation and a small in-frame insertion resulting in type 2A were also identified. Of 15 type 3 VWD IC, 13 were homozygous and two compound heterozygous for 14 candidate mutations predicted to result in lack of expression and two propeptide missense changes. Identification of intronic breakpoints of an exon 17–18 deletion suggested that the mutation resulted from non-homologous end joining. This study provides further insight into the pathogenesis of VWD in a population with a high degree of consanguineous partnerships.
Resistin-Like Molecule β Is Abundantly Expressed in Foam Cells and Is Involved in Atherosclerosis Development
Authors: Kushiyama Akifumi , Sakoda Hideyuki , Oue Naohide , Okubo Masamichi , Nakatsu Yusuke , Ono Haruya , Fukushima Toshiaki , Kamata Hideaki , Nishimura Fusanori , Kikuchi Takako , Fujishiro Midori , Nishiyama Koichi , Aburatani Hiroyuki , Kushiyama Sakura , Iizuka Masaki , Taki Naoyuki , Encinas Jeffrey , Sentani Kazuhiro , Ogonuki Narumi , Ogura Atsuo , Kawazu Shoji , Yasui Wataru , Higashi Yukihito , Kurihara Hiroki , Katagiri Hideki , Asano Tomoichiro 
Published: May 2013

Objective—
Resistin-like molecule (RELM) β is a secretory protein homologous to resistin and reportedly contributes to local immune response regulation in gut and bronchial epithelial cells. However, we found that activated macrophages also express RELMβ and thus investigated the role of RELMβ in the development of atherosclerosis.

Approach and Results—

It was demonstrated that foam cells in atherosclerotic lesions of the human coronary artery abundantly express RELMβ. RELMβ knockout (
−/−
) and wild-type mice were mated with apolipoprotein E–deficient background mice. RELMβ
−/−
apolipoprotein E–deficient mice exhibited less lipid accumulation in the aortic root and wall than RELMβ

+/+

apolipoprotein E–deficient mice, without significant changes in serum lipid parameters. In vitro, RELMβ
−/−
primary cultured peritoneal macrophages (PCPMs) exhibited weaker lipopolysaccharide-induced nuclear factor-κB classical pathway activation and inflammatory cytokine secretion than RELMβ
+/+
, whereas stimulation with RELMβ upregulated inflammatory cytokine expressions and increased expressions of many lipid transporters and scavenger receptors in PCPMs. Flow cytometric analysis revealed inflammatory stimulation–induced RELMβ in F4/80(+) CD11c(+) PCPMs. In contrast, the expressions of CD11c and tumor necrosis factor were lower in RELMβ
−/−
PCPMs, but both were restored by stimulation with recombinant RELMβ.

Conclusions—
RELMβ is abundantly expressed in foam cells within plaques and contributes to atherosclerosis development via lipid accumulation and inflammatory facilitation.
Therapeutic Silencing of MicroRNA-33 Inhibits the Progression of Atherosclerosis in
Ldlr
−/−
Mice—Brief Report
Authors: Rotllan Noemi , Ramírez Cristina M. , Aryal Binod , Esau Christine C. , Fernández-Hernando Carlos 
Published: May 2013

Objective—
To study the efficacy of anti–miRNA-33 therapy on the progression of atherosclerosis.

Approach and Results—

Ldlr
−/−
mice were injected subcutaneously with PBS, control, or anti–miR-33 oligonucleotides weekly and fed a Western diet for 12 weeks. At the end of treatment, the expression of miR-33 target genes was increased in the liver and aorta, demonstrating effective inhibition of miR-33 function. Interestingly, plasma high-density lipoprotein (HDL)-cholesterol was significantly increased in anti–miR-33-treated mice but only when they were fed a chow diet. However, HDL isolated from anti–miR-33-treated mice showed an increase cholesterol efflux capacity compared with HDL isolated from nontargeting oligonucleotide-treated mice. Analysis of atherosclerosis revealed a significant reduction of plaque size and macrophage content in mice receiving anti–miR-33. In contrast, no differences in collagen content and necrotic areas were observed among the 3 groups.

Conclusions—
Long-term anti–miR-33 therapy significantly reduces the progression of atherosclerosis and improves HDL functionality. The antiatherogenic effect is independent of plasma HDL-cholesterol levels.
Treatment of Obstructive Hypertrophic Cardiomyopathy Symptoms and Gradient Resistant to First-Line Therapy With β-Blockade or Verapamil
Authors: Sherrid Mark V. , Shetty Aneesha , Winson Glenda , Kim Bette , Musat Dan , Alviar Carlos L. , Homel Peter , Balaram Sandhya K. , Swistel Daniel G. 
Published: May 2013

Background—
There is controversy about preferred methods to relieve obstruction in hypertrophic cardiomyopathy patients still symptomatic after β-blockade or verapamil.

Methods and Results—

Of 737 patients prospectively registered at our institution, 299 (41%) required further therapy for obstruction for limiting symptoms, rest gradient 61±45, provoked gradient 115±49 mm Hg, and followed up for 4.8 years. Disopyramide was added in 221 (74%) patients and pharmacological control of symptoms was achieved in 141 (64%) patients. Overall, 138 (46%) patients had surgical relief of obstruction (91% myectomy) and 6 (2%) alcohol septal ablation. At follow-up, resting gradients in the 299 patients had decreased from 61±44 to 10±25 mm Hg (
P
<0.0001); New York Heart Association class decreased from 2.7±0.7 to 1.8±0.5 (
P
<0.0001). Kaplan–Meier survival at 10 years in the 299 advanced-care patients was 88% and did not differ from nonobstructed patients (
P
=0.28). Only 1 patient had sudden death, a low annual rate of 0.06%/y. Kaplan–Meier survival at 10 years in the advanced-care patients did not differ from that expected in a matched cohort of the US population (
P
=0.90).

Conclusions—
Patients with obstruction and symptoms resistant to initial pharmacological therapy with β-blockade or verapamil may realize meaningful symptom relief and low mortality through stepped management, adding disopyramide in appropriately selected patients, and when needed, by surgical myectomy.
Good Prognosis for Pericarditis With and Without Myocardial Involvement
Authors: Imazio Massimo , Brucato Antonio , Barbieri Andrea , Ferroni Francesca , Maestroni Silvia , Ligabue Guido , Chinaglia Alessandra , Cumetti Davide , Casa Giovanni Della , Bonomi Federica , Mantovani Francesca , Di Corato Paola , Lugli Roberta , Faletti Riccardo , Leuzzi Stefano , Bonamini Rodolfo , Modena Maria Grazia , Belli Riccardo 
Published: May 2013

Background—
The natural history of myopericarditis/perimyocarditis is poorly known, and recently published studies have presented contrasting data on their outcomes. The aim of the present article is to assess the prognosis of myopericarditis/perimyocarditis in a multicenter, prospective cohort study.

Methods and Results—

A total of 486 patients (median age, 39 years; range, 18–83 years; 300 men) with acute pericarditis or a myopericardial inflammatory syndrome (myopericarditis/perimyocarditis; 85% idiopathic, 11% connective tissue disease or inflammatory bowel disease, 5% infective) were prospectively evaluated from January 2007 to December 2011. The diagnosis of acute pericarditis was based on the presence of 2 of 4 clinical criteria (chest pain, pericardial rubs, widespread ST-segment elevation or PR depression, and new or worsening pericardial effusion). Myopericardial inflammatory involvement was suspected with atypical ECG changes for pericarditis, arrhythmias, and cardiac troponin elevation or new or worsening ventricular dysfunction on echocardiography and confirmed by cardiac magnetic resonance. After a median follow-up of 36 months, normalization of left ventricular function was achieved in >90% of patients with myopericarditis/perimyocarditis. No deaths were recorded, as well as evolution to heart failure or symptomatic left ventricular dysfunction. Recurrences (mainly as recurrent pericarditis) were the most common complication during follow-up and were recorded more frequently in patients with acute pericarditis (32%) than in those with myopericarditis (11%) or perimyocarditis (12%;
P
<0.001). Troponin elevation was not associated with an increase in complications.

Conclusions—
The outcome of myopericardial inflammatory syndromes is good. Unlike acute coronary syndromes, troponin elevation is not a negative prognostic marker in this setting.
Mortality From Myocardial Infarction After the Death of a Sibling: A Nationwide Follow‐up Study From Sweden
Authors: Rostila Mikael , Saarela Jan , Kawachi Ichiro 
Published: May 2013

Background
Death of a sibling represents a stressful life event and could be a potential trigger of myocardial infarction (MI). We studied the association between loss of an adult sibling and mortality from MI up to 18 years after bereavement.

Methods and Results

We conducted a follow‐up study for Swedes aged 40 to 69 years between 1981 and 2002, based on register data covering the total population (N=1 617 010). Sibling deaths could be observed from 1981 and on. An increased mortality rate from MI was found among women (1.25
CI
1.02 to 1.54) and men (1.15
CI
1.03 to 1.28) who had experienced death of an adult sibling. An elevated rate some years after bereavement was found among both women (during the fourth to sixth half‐years after the death) and men (during the second to sixth half‐years after the death), whereas limited support for a short‐term elevation in the rate was found (during the first few months since bereavement). External causes of sibling death were associated with increased
MI
mortality among women (1.54
CI
1.07 to 2.22), whereas nonexternal causes showed associations in men (1.23
CI
1.09 to 1.38). However, further analyses showed that if the sibling also died from MI, associations were primarily found among both women (1.62
CI
1.00 to 2.61) and men (1.98
CI
1.59 to 2.48).

Conclusions
Our study provided the first large‐scale evidence for mortality from MI associated with the death of a sibling at an adult age. The fact that findings suggested associations primarily between concordant causes of death (both died of MI) could indicate genetic resemblance or shared risk factors during childhood. Future studies on bereavement should carefully deal with the possibility of residual confounding.