bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment with dabigatran or warfarin in patients with venous thromboembolism and cancer
Authors: Goldhaber Samuel Z. , Kearon Clive , Kakkar Ajay K. , Schellong Sebastian , Eriksson Henry , Hantel Stefan , Feuring Martin , Kreuzer Jörg , Schulman Sam 
Published: March 2015

SummaryThe efficacy and safety of dabigatran for treatment of venous thromboembolism (VTE) were demonstrated in two trials. It is unclear if the results pertain to patients with cancer and VTE. Data from two randomised trials comparing dabigatran and warfarin for acute VTE were pooled. Primary efficacy outcome was symptomatic recurrent VTE and related death from randomisation to the end of the treatment period. Safety outcomes were major, major and clinically relevant non-major, and any bleeding during the oral-only treatment period. Patients with active cancer (=within 5 years) at baseline or diagnosed during the study were analysed. Compared with 4,772 patients without cancer, recurrent VTE occurred more frequently in 335 patients with cancer at any time (hazard ratio [HR] 3.3; 95 % confidence interval [CI], 2.1–5.3) and more often in 114 with cancer diagnosed during the study compared to 221 with cancer at baseline (HR 2.6; 95 % CI, 1.1–6.2). There was no significant difference in efficacy between dabigatran and warfarin for cancer at baseline (HR 0.75; 95 % CI, 0.20–2.8) or diagnosed during the study (HR 0.63; 95 % CI, 0.20–2.0). Major bleeding (HR 4.1; 95 % CI, 2.2–7.5) and any bleeding (HR 1.5; 95 % CI, 1.2–2.0) were more frequent in patients with cancer than without, but with similar incidence in cancer with dabigatran or warfarin. In conclusion, in cancer patients, dabigatran provided similar clinical benefit as warfarin. VTE recurrence or bleeding were similar in patients on dabigatran or warfarin. The efficacy of dabigatran has not been assessed in comparison with low-molecular-weight heparin.
Doce de série: as aventuras de dona Picucha
Authors: Duarte Elizabeth Bastos 
Published: March 2015

<p>O trabalho propõe-se a analisar as especificidades do formato adotado pelo seriado <em>Doce de mãe</em>, em comparação com as normas que presidem o subgênero <em>sitcom</em>, em relação ao tema central e temáticas secundárias privilegiadas, ao seu processo de actorialização e, mais particularmente, ao seu processo de tonalização, ou seja, à combinatória tonal conferida ao <em>sitcom</em>, que com ela interpela os telespectadores e dota de identidade o programa.</p><p> </p>
Genetic Ablation of PDGF-Dependent Signaling Pathways Abolishes Vascular Remodeling and Experimental Pulmonary Hypertension
Authors: ten Freyhaus Henrik , Berghausen Eva M. , Janssen Wiebke , Leuchs Maike , Zierden Mario , Murmann Kirsten , Klinke Anna , Vantler Marius , Caglayan Evren , Kramer Tilmann , Baldus Stephan , Schermuly Ralph T. , Tallquist Michelle D. , Rosenkranz Stephan 
Published: March 2015

Objective—
Despite modern therapies, pulmonary arterial hypertension (PAH) harbors a high mortality. Vascular remodeling is a hallmark of the disease. Recent clinical studies revealed that antiremodeling approaches with tyrosine–kinase inhibitors such as imatinib are effective, but its applicability is limited by significant side effects. Although imatinib has multiple targets, expression analyses support a role for platelet-derived growth factor (PDGF) in the pathobiology of the disease. However, its precise role and downstream signaling events have not been established.

Approach and Results—

Patients with PAH exhibit enhanced expression and phosphorylation of β PDGF receptor (βPDGFR) in remodeled pulmonary arterioles, particularly at the binding sites for phophatidyl-inositol-3-kinase and PLCγ at tyrosine residues 751 and 1021, respectively. These signaling molecules were identified as critical downstream mediators of βPDGFR-mediated proliferation and migration of pulmonary arterial smooth muscle cells. We, therefore, investigated mice expressing a mutated βPDGFR that is unable to recruit phophatidyl-inositol-3-kinase and PLCγ (βPDGFR
F3/F3
). PDGF-dependent Erk1/2 and Akt phosphorylation, cyclin D1 induction, and proliferation, migration, and protection against apoptosis were abolished in βPDGFR
F3/F3
pulmonary arterial smooth muscle cells. On exposure to chronic hypoxia, vascular remodeling of pulmonary arteries was blunted in βPDGFR
F3/F3
mice compared with wild-type littermates. These alterations led to protection from hypoxia-induced PAH and right ventricular hypertrophy.

Conclusions—
By means of a genetic approach, our data provide definite evidence that the activated βPDGFR is a key contributor to pulmonary vascular remodeling and PAH. Selective disruption of PDGF-dependent phophatidyl-inositol-3-kinase and PLCγ activity is sufficient to abolish these pathogenic responses in vivo, identifying these signaling events as valuable targets for antiremodeling strategies in PAH.
Phosphoregulation of Cardiac Inotropy via Myosin Binding Protein-C During Increased Pacing Frequency or β
1
-Adrenergic Stimulation
Authors: Tong Carl W. , Wu Xin , Liu Yang , Rosas Paola C. , Sadayappan Sakthivel , Hudmon Andy , Muthuchamy Mariappan , Powers Patricia A. , Valdivia Héctor H. , Moss Richard L. 
Published: March 2015

Background—
Mammalian hearts exhibit positive inotropic responses to β-adrenergic stimulation as a consequence of protein kinase A–mediated phosphorylation or as a result of increased beat frequency (the Bowditch effect). Several membrane and myofibrillar proteins are phosphorylated under these conditions, but the relative contributions of these to increased contractility are not known. Phosphorylation of cardiac myosin-binding protein-C (cMyBP-C) by protein kinase A accelerates the kinetics of force development in permeabilized heart muscle, but its role in vivo is unknown. Such understanding is important because adrenergic responsiveness of the heart and the Bowditch effect are both depressed in heart failure.

Methods and Results—

The roles of cMyBP-C phosphorylation were studied using mice in which either WT or nonphosphorylatable forms of cMyBP-C [ser273ala, ser282ala, ser302ala: cMyBP-C(t3SA)] were expressed at similar levels on a cMyBP-C null background. Force and [Ca
2+
]
in
measurements in isolated papillary muscles showed that the increased force and twitch kinetics because increased pacing or β
1
-adrenergic stimulation were nearly absent in cMyBP-C(t3SA) myocardium, even though [Ca
2+
]
in
transients under each condition were similar to WT. Biochemical measurements confirmed that protein kinase A phosphorylated ser273, ser282, and ser302 in WT cMyBP-C. In contrast, CaMKIIδ, which is activated by increased pacing, phosphorylated ser302 principally, ser282 to a lesser degree, and ser273 not at all.

Conclusions—
Phosphorylation of cMyBP-C increases the force and kinetics of twitches in living cardiac muscle. Further, cMyBP-C is a principal mediator of increased contractility observed with β-adrenergic stimulation or increased pacing because of protein kinase A and CaMKIIδ phosphorylations of cMyB-C.
Progressive Cognitive Deficits in a Mouse Model of Recurrent Photothrombotic Stroke
Authors: Schmidt Antje , Diederich Kai , Strecker Jan-Kolja , Geng Birgit , Hoppen Maike , Duning Thomas , Schäbitz Wolf-Rüdiger , Minnerup Jens 
Published: March 2015

Background and Purpose—
In spite of its high disease burden, there is no specific treatment for multi-infarct dementia. The preclinical evaluation of candidate drugs is limited because an appropriate animal model is lacking. Therefore, we aimed to evaluate whether a mouse model of recurrent photothrombotic stroke is suitable for the preclinical investigation of multi-infarct dementia.

Methods—
Recurrent photothrombotic cortical infarcts were induced in 25 adult C57BL/6 mice. Twenty-five sham-operated animals served as controls. The object recognition test and the Morris water maze test were performed >6 weeks to assess cognitive deficits. Afterward, histological analyses were performed to characterize histopathologic changes associated with recurrent photothrombotic infarcts.

Results—

After the first infarct, the object recognition test showed a trend toward an impaired formation of recognition memories (
P
=0.08), and the Morris Water Maze test revealed significantly impaired spatial learning and memory functions (
P
<0.05). After recurrent infarcts, the object recognition test showed significant recognition memory deficits (
P
<0.001) and the Morris water maze test demonstrated persisting spatial learning and memory deficits (
P
<0.05). Histological analyses revealed remote astrogliosis in the hippocampus.

Conclusions—
Our results show progressive cognitive deficits in a mouse model of recurrent photothrombotic stroke. The presented model resembles the clinical features of human multi-infarct dementia and enables the investigation of its pathophysiological mechanisms and the evaluation of treatment strategies.
New record of Anelytra (Anelytra) eunigrifrons Ingrisch, 1998 (Orthoptera, Tettigoniidae: Conocephalinae, Agraeciini) from India
Authors: NAGAR RAJENDRA , MAL JHABAR , SWAMINATHAN R. 
Published: March 2015

The record of Anelytra (Anelytra) eunigrifrons Ingrisch, 1998 (Conocephlinae: Agraeciini) collected from Umiam in the North-east province, Meghalaya (India) is reported for the first time. Previously, the species was reported from Indo-China, Myanmar Burma, and Shan province, Carin Ghecu (Ingrisch, February 01, 1888 to March 31, 1888 and 1998). From India only one species, Anelytra (Anelytra) concolor Redtenbacher, 1891 has been recorded from Maharashtra, Mumbai. The paper includes the morphological characterization of the male of this species collected from North-east India.
USH2 Caused by GPR98 Mutation Diagnosed by Massively Parallel Sequencing in Advance of the Occurrence of Visual Symptoms
Authors: Moteki Hideaki , Yoshimura Hidekane , Azaiez Hela , Booth Kevin T. , Shearer A. Eliot , Sloan Christina M. , Kolbe Diana L. , Murata Toshinori , Smith Richard J. H. , Usami Shin-ichi 
Published: March 2015

Objective: We present 2 patients who were identified with mutations in the GPR98 gene that causes Usher syndrome type 2 (USH2). Methods: One hundred ninety-four (194) Japanese subjects from unrelated families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were used to identify the genetic causes of hearing loss. Results: We identified causative mutations in the GPR98 gene in 1 family (2 siblings). The patients had moderate sloping hearing loss, and no progression was observed over a period of 10 years. Fundus examinations were normal. However, electroretinograms revealed impaired responses in both patients. Conclusion: Early diagnosis of Usher syndrome has many advantages for patients and their families. This study supports the use of comprehensive genetic diagnosis for Usher syndrome, especially prior to the onset of visual symptoms, to provide the highest chance of diagnostic success in early life stages.
The role of hematologists in a changing United States health care system
Authors: Wallace Paul J. , Connell Nathan T. , Abkowitz Janis L. 
Published: March 2015

Abstract
Major and ongoing changes in health care financing and delivery in the United States have altered opportunities and incentives for new physicians to specialize in nonmalignant hematology. At the same time, effective clinical tools and strategies continue to rapidly emerge. Consequently, there is an imperative to foster workforce innovation to ensure sustainable professional roles for hematologists, reliable patient access to optimal hematology expertise, and optimal patient outcomes. The American Society of Hematology is building a collection of case studies to guide the creation of institutionally supported systems-based clinical hematologist positions that predominantly focus on nonmalignant hematology. These roles offer a mix of guidance regarding patient management and the appropriate use and stewardship of clinical resources, as well as development of new testing procedures and protocols.
Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNFα
Authors: Castro-Villegas Carmen , Pérez-Sánchez Carlos , Escudero Alejandro , Filipescu Ileana , Verdu Miriam , Ruiz-Limón Patricia , Aguirre Ma Angeles , Jiménez-Gomez Yolanda , Font Pilar , Rodriguez-Ariza Antonio , Peinado Juan Ramon , Collantes-Estévez Eduardo , González-Conejero Rocío , Martinez Constantino , Barbarroja Nuria , López-Pedrera Chary 
Published: March 2015

Abstract
Introduction
The advent of anti-tumor necrosis factor alpha (anti-TNFα) drugs has considerably improved medical management in rheumatoid arthritis (RA) patients, although it has been reported to be ineffective in a fraction of them. MicroRNAs (miRNAs) are small, non-coding RNAs that act as fine-tuning regulators of gene expression. Targeting miRNAs by gain or loss of function approaches have brought therapeutic effects in various disease models. The aim of this study was to investigate serum miRNA levels as predictive biomarkers of response to anti-TNFα therapy in RA patients.

Methods
In total, 95 RA patients undergoing anti-TNFα/disease-modifying antirheumatic drugs (anti-TNFα/DMARDs) combined treatments were enrolled. Serum samples were obtained at 0 and 6 months and therapeutic efficacy was assessed. miRNAs were isolated from the serum of 10 patients before and after anti-TNFα/DMARDs combination therapy, cDNA transcribed and pooled, and human serum miRNA polymerase chain reaction (PCR) arrays were performed. Subsequently, selected miRNAs were analyzed in a validation cohort consisting of 85 RA patients. Correlation studies with clinical and serological variables were also performed.

Results
Ninety percent of RA patients responded to anti-TNFα/DMARDs combination therapy according to European League Against Rheumatism (EULAR) criteria. Array analysis showed that 91% of miRNAS were overexpressed and 9% downregulated after therapy. Functional classification revealed a preponderance of target mRNAs involved in reduction of cells maturation - especially on chondrocytes - as well as in immune and inflammatory response, cardiovascular disease, connective tissue and musculoskeletal system. Six out of ten miRNAs selected for validation were found significantly upregulated by anti-TNFα/DMARDs combination therapy (miR-16-5p, miR-23-3p, miR125b-5p, miR-126-3p, miRN-146a-5p, miR-223-3p). Only responder patients showed an increase in those miRNAs after therapy, and paralleled the reduction of TNFα, interleukin (IL)-6, IL-17, rheumatoid factor (RF), and C-reactive protein (CRP). Correlation studies demonstrated associations between validated miRNAs and clinical and inflammatory parameters. Further, we identified a specific plasma miRNA signature (miR-23 and miR-223) that may serve both as predictor and biomarker of response to anti-TNFα/DMARDs combination therapy.

Conclusions
miRNA levels in the serum of RA patients before and after anti-TNFα/DMARDs combination therapy are potential novel biomarkers for predicting and monitoring therapy outcome.
Significant effects of biologic therapy on lipid profiles and insulin resistance in patients with rheumatoid arthritis
Authors: Chen Der-Yuan , Chen Yi-Ming , Hsieh Tsu-Yi , Hsieh Chia-Wei , Lin Chi-Chen , Lan Joung-Liang 
Published: March 2015

Abstract
Introduction
The goal of this study was to investigate (1) the associations of rheumatoid arthritis (RA)-related inflammation or rheumatoid factor/anti-cyclic citrullinated peptide (anti-CCP) positivity with lipid profiles and insulin resistance (IR), (2) the effects of biologic therapy on lipid profiles and IR, and (3) potential predictors for the presence of subclinical atherosclerosis.

Methods
Serum levels of lipid profiles were determined by enzymatic methods in 32 adalimumab-treated patients, 16 etanercept-treated patients, 24 tocilizumab-treated patients, and 20 biologic-naïve patients. Atherogenic index, which corresponds to the ratio of total cholesterol to high-density lipoprotein cholesterol (HDL-C), was calculated. IR was measured by homeostasis model assessment. Pro-inflammatory cytokine levels were examined by enzyme-linked immunosorbent assay. Common carotid artery intima-media thickness was determined by using sonography.

Results
There was an inverse correlation between disease activity (disease activity score for 28 joints, or DAS28) and low-density lipoprotein cholesterol (LDL-C) levels (r = −0.226, P <0.05) and a positive correlation between DAS28 and IR (r = 0.361, P <0.005). Anti-CCP-positive patients had significantly higher DAS28 and IR compared with anti-CCP-negative patients. There was also a positive correlation between IR and levels of interleukin-6 or tumor necrosis factor-alpha (TNF-α). HDL-C levels significantly increased in patients receiving 6-month anti-TNF-α therapy, and levels of total cholesterol, LDL-C, and triglyceride increased in tocilizumab-treated patients. IR significantly decreased in patients under biologic therapy but was unchanged in biologic-naïve patients. Age, IR, and DAS28 were significant predictors of severe subclinical atherosclerosis (odds ratios of 1.08, 2.77, and 2.52, respectively).

Conclusions
Significant associations of RA-related inflammation with lipid profiles and IR indicate the involvement of RA in atherosclerosis pathogenesis. Biologic therapies were associated with IR reduction without change in atherogenic index, but their beneficial effects on atherosclerosis reduction need to be verified in the future.
Clinical characteristics and treatment-related biomarkers associated with response to high-dose interleukin-2 in metastatic melanoma and renal cell carcinoma: retrospective analysis of an academic community hospital’s experience
Authors: Saraceni Christine , Agostino Nicole , Weiss Michael J , Harris Katherine , Nair Suresh 
Published: March 2015

Abstract

Background
Immunotherapy in the treatment of metastatic melanoma and renal cell carcinoma can produce durable therapeutic responses, which may improve survival. We aimed to identify clinical characteristics and biomarkers associated with response to high-dose interleukin-2 therapy (IL-2) in patients with metastatic melanoma and renal cell carcinoma treated at an academic community hospital.

Patients/Methods
We retrospectively analyzed clinical variables and biomarkers of 50 consecutive metastatic melanoma or renal cell carcinoma patients treated at our institution with IL-2 during 2004 – 2012. We evaluated clinical characteristics: metastatic sites of disease, prior therapies, number of IL-2 doses per cycle, response duration, autoimmune phenomena, and peak fever, as well as laboratory biomarkers: baseline LDH, platelet nadir, and baseline and highest absolute lymphocyte count (ALC). Survival outcomes were calculated using Kaplan-Meier curves.

Results
Variables differing between responders (clinical benefit group) and non-responders (no clinical benefit group) in metastatic melanoma included platelet nadir during treatment (p = 0.015), autoimmune phenomena (p = 0.049), and in renal cell carcinoma, platelet nadir (p = 0.026). There were no significant differences between number of doses of IL-2 received per cycle and response in either cancer subtype. Clinical benefit occurred in 25% of patients (9/36) when IL-2 was given as first-line therapy. Median overall survival for the clinical benefit group from the initiation of IL-2 to death or last follow-up was 61 months versus 17 months for the no clinical benefit group (p < 0.001) for metastatic melanoma. In renal cell carcinoma overall survival for clinical benefit patients was 48 months versus 17 months. No treatment-related deaths occurred.

Conclusions
High-dose IL-2 can be safely administered by an experienced team in a non–intensive care oncology unit. The clinical benefit group developed autoimmune phenomena (melanoma patients), lower platelet nadir, and on average, received the same number of IL-2 doses as the no clinical benefit group, suggesting a response relationship to the patient’s baseline immune status. Further investigation of immune predictors of response may be useful to select appropriate patients for this therapy.
Mode I critical fracture energy of adhesively bonded joints between glass fiber reinforced thermoplastics
Authors: Mahaphasukwat Siripong , Shimamoto Kazumasa , Hayashida Shota , Sekiguchi Yu , Sato Chiaki 
Published: March 2015

Abstract
Critical fracture energies of adhesively bonded joints under mode I constant separation were experimentally investigated. Double cantilever beam (DCB) specimens comprising polyamide 6 (PA6) based fiber reinforced thermoplastics (GFRTP) were utilized for the experiments. The adherends of the joints were bonded with three different types of adhesives such as polyurethane and acrylates. A surface treatment method with a primer was applied to pre-bonded surface, matching with the different adhesives, which results in five combinations.
Strongest combination, Plexus Primer PC120 and Plexus AO420, exhibited 2.95 kJ/m2 in mode I critical fracture energy, which is much higher than those of ordinary epoxy adhesive and similar to those of rubber-modified very-ductile epoxy adhesives. Therefore, it is confirmed that adhesive bonding can be applied to join PA6 based GFRTP even for structural use, although the material is thought too difficult to bond adhesively.
Krüppel-like factor 4 is a transcriptional regulator of M1/M2 macrophage polarization in alcoholic liver disease
Authors: Saha Banishree , Bala Shashi , Hosseini Nooshin , Kodys Karen , Szabo Gyongyi 
Published: March 2015

Abstract
Macrophages play an important role in inflammation and liver injury. In ALD, activated macrophages, including M1 (proinflammatory) and M2 (anti-inflammatory) macrophages, are present in the liver. As KLF4 has been described as a regulator of macrophage polarization, we investigated its role in ALD. Chronic alcohol feeding in C57Bl/6 mice led to increased expression of M1 (TNF-α, MCP1, and IL-1β) and M2 (Arg1, Mrc1, and IL-10) genes and the frequency of CD206+CD163+ M2 macrophages in the liver. KLF4 mRNA and protein levels were increased in the livers of EtFed compared with PF mice. In macrophages, in vivo and in vitro, EtOH increased KLF4 levels, transcriptional activity, and expression of M1 and M2 genes. KLF4 knockdown and overexpression experiments demonstrated alcohol-dependent and -independent functions of KLF4 in regulating M1 and M2 markers. KLF4 siRNA treatment, alone and in synergy with alcohol, increased the levels of M1 markers. In contrast, KLF4 overexpression increased the levels of M2 and decreased M1 markers, and this was enhanced further by alcohol. KLF4 was regulated by alcohol and its metabolites. KLF4 mRNA and activity were increased in the presence of 4-MP, an inhibitor of ADH, and CYP2E1. However, inhibition of acetaldehyde breakdown attenuated KLF4 induction and promoted M1 polarization. We conclude that KLF4 regulates M1 and M2 markers in ALD. EtOH promotes KLF4 and M2 phenotype, whereas acetaldehyde attenuates KLF4 and promotes M1 macrophage, which may explain the increased presence of M1 and M2 macrophage populations in ALD.