bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemotherapy Induces Intratumoral Expression of Chemokines in Cutaneous Melanoma, Favoring T-cell Infiltration and Tumor Control
Authors: Hong Michelle , Puaux Anne-Laure , Huang Caleb , Loumagne Laure , Tow Charlene , Mackay Charles , Kato Masashi , Prévost-Blondel Armelle , Avril Marie-Françoise , Nardin Alessandra , Abastado Jean-Pierre 
Published: September 2011

Abstract
T-cell infiltration is known to impact tumor growth and is associated with cancer patient survival. However, the molecular cues that favor T-cell infiltration remain largely undefined. Here, using a genetically engineered mouse model of melanoma, we show that CXCR3 ligands and CCL5 synergize to attract effector T cells into cutaneous metastases, and their expression inhibits tumor growth. Treatment of tumor-bearing mice with chemotherapy induced intratumoral expression of these chemokines and favored T-cell infiltration into cutaneous tumors. In patients with melanoma, these chemokines were also upregulated in chemotherapy-sensitive lesions following chemotherapy, and correlated with T-cell infiltration, tumor control, and patient survival. We found that dacarbazine, temozolomide, and cisplatin induced expression of T-cell–attracting chemokines in several human melanoma cell lines in vitro. These data identify the induction of intratumoral expression of chemokines as a novel cell-extrinsic mechanism of action of chemotherapy that results in the recruitment of immune cells with antitumor activity. Therefore, identifying chemotherapeutic drugs able to induce the expression of T-cell–attracting chemokines in cancer cells may represent a novel strategy to improve the efficacy of cancer immunotherapy. Cancer Res; 71(22); 6997–7009. ©2011 AACR.
Molecular Imaging of TGFβ-Induced Smad2/3 Phosphorylation Reveals a Role for Receptor Tyrosine Kinases in Modulating TGFβ Signaling
Authors: Nyati Shyam , Schinske Katrina , Ray Dipankar , Nyati Mukesh , Ross Brian Dale , Rehemtulla Alnawaz 
Published: September 2011

Abstract
Purpose: The dual modality of TGFβ, both as a potent tumor suppressor and a stimulator of tumor progression, invasion, and metastasis, make it a critical target for therapeutic intervention in human cancers. The ability to carry out real-time, noninvasive imaging of TGFβ-activated Smad signaling in live cells and animal models would significantly improve our understanding of the regulation of this unique signaling cascade. To advance these efforts, we developed a highly sensitive molecular imaging tool that repetitively, noninvasively, and dynamically reports on TGFBR1 kinase activity.
Experimental Design: The bioluminescent TGFβR1 reporter construct was developed using a split firefly luciferase gene containing a functional sensor of Smad2 phosphorylation, wherein inhibition of TGFβ receptor1 kinase activity leads to an increase in reporter signaling. The reporter was stably transfected into mammalian cells and used to image in vivo and in vitro bioluminescent activity as a surrogate for monitoring TGFBR1 kinase activity.
Results: The reporter was successfully used to monitor direct and indirect inhibition of TGFβ-induced Smad2 and SMAD3 phosphorylation in live cells and tumor xenografts and adapted for high-throughput screening, to identify a role for receptor tyrosine kinase inhibitors as modulators of TGFβ signaling.
Conclusion: The reporter is a dynamic, noninvasive imaging modality for monitoring TGFβ-induced Smad2 signaling in live cells and tumor xenografts. It has immense potential for identifying novel effectors of R-Smad phosphorylation, for validating drug–target interaction, and for studying TGFβ signaling in different metastasis models. Clin Cancer Res; 17(23); 7424–39. ©2011 AACR.
Vascular Response to Zotarolimus-Coated Balloons in Injured Superficial Femoral Arteries of the Familial Hypercholesterolemic Swine
Authors: Granada Juan F. , Milewski Krzysztof , Zhao Hugh , Stankus John J. , Tellez Armando , Aboodi Michael S. , Kaluza Greg L. , Krueger Christian G. , Virmani Renu , Schwartz Lewis B. , Nikanorov Alexander 
Published: September 2011

Background—
Drug-coated balloons are rapidly emerging as a therapeutic alternative for the interventional treatment of peripheral vascular disease. The purpose of this study was to test the hypothesis that an angioplasty balloon coated with the mTOR inhibitor zotarolimus (ZCB) would inhibit neointimal hyperplasia in a novel injury-based superficial femoral artery model in the familial hypercholesterolemic swine.

Methods and Results—

A total of 44 familial hypercholesterolemic swine were included (12 designated to study tissue pharmacokinetics and 32 to study safety and efficacy). Fogarty balloon denudation was performed in all superficial femoral artery segments, followed by balloon angioplasty. In the pharmacokinetic study, a total of 24 ZCBs (300 μg/cm
2
) were used. Zotarolimus was detected in arterial tissue at 5 minutes (162 ng/mg of tissue), 24 hours (5.9 ng/mg of tissue), and 28 days (0.007 ng/mg of tissue) after ZCB inflation. In the safety and efficacy study, superficial femoral artery segments were randomized to either high-dose (600 μg/cm
2
, n=16), low-dose (300 μg/cm
2
, n=16), or paired uncoated balloons (high-dose ZCB control, n=16; low-dose ZCB control, n=16). At 28 days, the percentage of angiographic stenosis was similar among all tested groups. Histological analysis demonstrated a reduction in neointimal formation in both ZCB groups compared with controls (high-dose ZCB 44% reduction,
P
=0.007; low-dose ZCB 22% reduction,
P
=0.08). There was no evidence of delayed arterial healing or vascular toxicity in any of the ZCB groups.

Conclusions—
The single delivery of zotarolimus via coated balloon is feasible, and therapeutic levels are maintained up to 28 days. The ZCB technology appears to be effective in the reduction of neointimal proliferation in the superficial femoral artery of the familial hypercholesterolemic swine.
Mental health professionals’ attitudes towards people with mental illness: Do they differ from attitudes held by people with mental illness?
Authors: Hansson Lars , Jormfeldt Henrika , Svedberg Petra , Svensson Bengt 
Published: September 2011

Aims: Studies investigating mental health professionals’ attitudes towards people with mental illness are scarce and there is a lack of comparative studies including both patients’ and mental health professionals’ attitudes. The aim of the present study was to investigate mental health staff’s attitudes towards people with mental illness and compare these with the attitudes of patients in contact with mental health services. A further aim was to relate staff attitudes to demographic and work characteristics. Methods: A cross-sectional study was performed including 140 staff and 141 patients. The study included a random sample of outpatients in contact with mental health services in the southern part of Sweden and staff working in these services. Attitudes were investigated using a questionnaire covering beliefs of devaluation and discrimination of people with a mental illness. Results: Negative attitudes were prevalent among staff. Most negative attitudes concerned whether an employer would accept an application for work, willingness to date a person who had been hospitalized, and hiring a patient to take care of children. Staff treating patients with a psychosis or working in inpatient settings had the most negative attitudes. Patient attitudes were overall similar to staff attitudes and there were significant differences in only three out of 12 dimensions. Patients’ most negative attitudes were in the same area as the staff’s. Conclusions: This study points to the suggestion that mental health care staff may hold negative attitudes and beliefs about people with mental illness with tentative implications for treatment of the patient and development and implementation of evidence-based services. Since patients and staff in most respects share these beliefs, it is essential to develop interventions that have an impact on both patients and staff, enabling a more recovery-oriented staff–patient relationship.
Effect of Silymarin in the Treatment of Allergic Rhinitis
Authors: Bakhshaee Mehdi , Jabbari Farahzad , Hoseini Saeed , Farid Reza , Sadeghian Mohammad Hadi , Rajati Mohsen , Mohamadpoor Amir Houshang , Movahhed Rahman , Zamani Mohammad Ali 
Published: September 2011

ObjectiveAlthough the role of oxidative stresses has been confirmed in the pathophysiology of allergic rhinitis and the protective effect of silymarin against oxidative stresses has been proven in different organs, no study has yet been conducted on the impact of silymarin on allergic rhinitis treatment.Study DesignA randomized clinical trial study.SettingTwo tertiary referral centers with otorhinolaryngology–head and neck surgery and allergy and immunology departments.Patients and MethodsIn a randomized clinical trial, 94 patients with the signs and symptoms of allergic rhinitis and a positive skin prick test were selected and randomly divided into 2 groups. Their signs and symptoms, eosinophil percentage on nasal smear, serum IgE, and interleukin (IL‐4, IL‐5, interferon‐γ) levels were recorded. The study group was treated with silymarin, whereas the control group received placebo, both for 1 month, along with routine antihistamine treatment. At the end of the treatment course, clinical and laboratory findings were statistically analyzed.ResultsSixty patients completed the trial. Based on the Sino‐Nasal Outcome Test 20 (SNOT‐20), a significant improvement in clinical symptom severity was observed in both groups (9.23 ± 5.14 vs 2.20 ± 2.69; P <. 001), which was statistically significantly higher in the study group (P <. 001). Posttreatment percentage of nasal eosinophils and cytokine levels showed no significant difference (P >. 05). Rise in serum IgE level was seen after treatment with silymarin (P =. 003).ConclusionConsidering the statistically effective role of silymarin in alleviating the severity of allergic rhinitis symptoms, applying this herbal antioxidant along with other medications may result in better management.
Cartilage Injury After Acute, Isolated Anterior Cruciate Ligament Tear
Authors: Potter Hollis G. , Jain Sapna K. , Ma Yan , Black Brandon R. , Fung Sebastian , Lyman Stephen 
Published: September 2011

Background: Anterior cruciate ligament (ACL) tears have been implicated in the development of osteoarthritis. Limited data exist on longitudinal follow-up of isolated ACL injury. Hypotheses: All isolated ACL tears are associated with some degree of cartilage injury that will deteriorate over time. There is a threshold of magnetic resonance imaging (MRI)–detectable cartilage injury that will correlate with adverse change in subjective patient-reported outcome measures. Study Design: Cohort study, Level of evidence, 2. Methods: The authors conducted a prospective, observational analysis of 42 knees in 40 patients with acute, isolated ACL injury (14 treated nonoperatively, 28 by reconstruction) with imaging at the time of injury and yearly follow-up for a maximum of 11 years. Morphologic MRI and quantitative T2 mapping was performed with validated outcome measures. Results: All patients sustained chondral damage at initial injury. The adjusted risk of cartilage loss doubled from year 1 for the lateral compartment and medial femoral condyle (MFC) and tripled for the patella. By years 7 to 11, the risk for the lateral femoral condyle was 50 times baseline, 30 times for the patella, and 19 times for the MFC. There was increased risk of cartilage degeneration over the medial tibial plateau (MTP) ( P = .047; odds ratio = 6.23; 95% confidence interval [CI], 1.03-37.90) and patella ( P = .032; odds ratio = 4.88; 95% CI, 1.14-20.80) in nonsurgical patients compared with surgically treated patients. Size of the bone-marrow edema pattern was associated with cartilage degeneration from baseline to year 3 ( P = .001 to .039). Each increase in the MFC Outerbridge score resulted in a 13-point decrease in the International Knee Documentation Committee subjective knee score ( P = .0002). Each increase in the MTP resulted in a 2.4-point decrease in the activity rating scale ( P = .002). Conclusion: All patients with acute, traumatic ACL disruption sustained a chondral injury at the time of initial impact with subsequent longitudinal chondral degradation in compartments unaffected by the initial “bone bruise,” a process that is accelerated at 5 to 7 years’ follow-up.
Investigations for a model reduction technique of fluid–structure coupled systems
Authors: Ben Smida B , Majed R , Bouhaddi N , Ouisse M 
Published: September 2011

In this paper, a methodology for coupled fluid–structure model reduction is proposed. The overall objective of the method is to reduce the numerical computational costs without affecting the accuracy level of the prediction. This methodology is organized according to the three following steps. In the first step, this method uses a reliable criterion for selecting the number of the kept modes for the fluid and the structure in vacuo subsystems. In the second step, this basis will be enriched through static residual responses taking into account the fluid–structure coupling effects. These responses are selected according to an energetic criterion. Finally, the enriched basis is extended by introducing some residual static responses due to the error forces considered as structural modifications forces. In the context of the finite element method (FEM), the performances of the proposed method are established through a comparative study with other strategies that are proposed in the literature. Thus, the computational cost (CPU time) and the accuracies of the different methods are discussed and compared with a reference method. The validation of the proposed method and the comparative study are performed through two numerical simulation examples. The first one concerns a parallelepiped acoustic cavity with a simply supported plate. The method can handle both weak and strong couplings; as illustrated in the examples. The second one consists of a pipe with a strong coupling and a larger model size.
The role of CD8+ T cells in a model of multiple sclerosis induced with recombinant myelin oligodendrocyte glycoprotein
Authors: Sajic Marija , Gregson Norman , Linington Christopher , Hughes Richard AC , Smith Kenneth J 
Published: September 2011

Background and objectives: Since CD8+ T cells may be important in the pathogenesis of multiple sclerosis (MS), we examined their role in the DA rat experimental autoimmune encephalomyelitis (EAE) model induced by immunization with recombinant myelin oligodendrocyte glycoprotein (rMOG). Methods: The inflammatory infiltrate in the spinal cord of affected animals was assessed by histology, electrophysiology and flow cytometry during the course of the disease (the first peak, remission and the second peak). The proportions of activated/memory effector (CD8+CD44+) and putative suppressor (CD8+CD28-, CD8+CD25high) CD8+ T cells in the draining lymph nodes were determined. To explore the role of CD8+ T cells, similar experiments were performed in CD8+ T cell depleted rats, before, during and after the first peak of the disease. Results: Throughout the disease, both CD4+ T cells and macrophages/activated microglia outnumbered CD8+ T cells within the spinal cord. The number of putative suppressor CD8+ T cells increased significantly both during and after the first peak suggesting the induction of a regulatory CD8+ T-cell response. However, antibody-mediated depletion of CD8+ T cells before induction of the disease, or after the first peak, did not significantly alter the incidence, severity or course of rMOG-induced EAE. Conclusions: The findings suggest that CD8+ T cells do not play a significant role in the pathogenesis or regulation of EAE induced by rMOG in DA rats. In this respect, rMOG-induced EAE is not an appropriate model for studying the role of CD8+ T cells in MS.
Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment
Authors: Morabito Fortunato , Gentile Massimo , Mazzone Carla , Rossi Davide , Di Raimondo Francesco , Bringhen Sara , Ria Roberto , Offidani Massimo , Patriarca Francesca , Nozzoli Chiara , Petrucci Maria Teresa , Benevolo Giulia , Vincelli Iolanda , Guglielmelli Tommasina , Grasso Mariella , Marasca Roberto , Baldini Luca , Montefusco Vittorio , Musto Pellegrino , Cascavilla Nicola , Majolino Ignazio , Musolino Caterina , Cavo Michele , Boccadoro Mario , Palumbo Antonio 
Published: September 2011

AbstractWe assessed efficacy, safety, and reversal of renal impairment (RI) in untreated patients with multiple myeloma given bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide (VMPT-VT) maintenance or bortezomib-melphalan-prednisone (VMP). Exclusion criteria included serum creatinine ≥ 2.5 mg/dL. In the VMPT-VT/VMP arms, severe RI (estimated glomerular filtration rate [eGFR] ≤ 30 mL/min), moderate RI (eGFR 31-50 mL/min), and normal renal function (eGFR > 50 mL/min), were 6%/7.9%, 24.1%/24.9%, and 69.8%/67.2%, respectively. Statistically significant improvements in overall response rates and progression-free survival were observed in VMPT-VT versus VMP arms across renal cohorts, except in severe RI patients. In the VMPT group, severe RI reduced overall survival (OS). RI was reversed in 16/63 (25.4%) patients receiving VMPT-VT versus 31/77 (40.3%) receiving VMP. Multivariate analysis showed male sex (P = .022) and moderate RI (P = .003) significantly predicted RI recovery. VMP patients achieving renal response showed longer OS. In both arms, greater rates of severe hematologic adverse events were associated with RI (eGFR < 50 mL/min), however, therapy discontinuation rates were unaffected. VMPT-VT was superior to VMP for cases with normal renal function and moderate RI, whereas VMPT-VT failed to outperform VMP in patients with severe RI, although the relatively low number of cases analyzed preclude drawing definitive conclusions. VMPT-VT had no advantage in terms of RI reversal over VMP. This study is registered at http://www.clinicaltrials.gov as NCT01063179.
Erythrocyte membrane changes of chorea-acanthocytosis are the result of altered Lyn kinase activity
Authors: De Franceschi Lucia , Tomelleri Carlo , Matte Alessandro , Brunati Anna Maria , Bovee-Geurts Petra H. , Bertoldi Mariarita , Lasonder Edwin , Tibaldi Elena , Danek Adrian , Walker Ruth H. , Jung Hans H. , Bader Benedikt , Siciliano Angela , Ferru Emanuela , Mohandas Narla , Bosman Giel J. C. G. M. 
Published: September 2011

AbstractAcanthocytic RBCs are a peculiar diagnostic feature of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder. Although recent years have witnessed some progress in the molecular characterization of ChAc, the mechanism(s) responsible for generation of acanthocytes in ChAc is largely unknown. As the membrane protein composition of ChAc RBCs is similar to that of normal RBCs, we evaluated the tyrosine (Tyr)–phosphorylation profile of RBCs using comparative proteomics. Increased Tyr phosphorylation state of several membrane proteins, including band 3, β-spectrin, and adducin, was noted in ChAc RBCs. In particular, band 3 was highly phosphorylated on the Tyr-904 residue, a functional target of Lyn, but not on Tyr-8, a functional target of Syk. In ChAc RBCs, band 3 Tyr phosphorylation by Lyn was independent of the canonical Syk-mediated pathway. The ChAc-associated alterations in RBC membrane protein organization appear to be the result of increased Tyr phosphorylation leading to altered linkage of band 3 to the junctional complexes involved in anchoring the membrane to the cytoskeleton as supported by coimmunoprecipitation of β-adducin with band 3 only in ChAc RBC-membrane treated with the Lyn-inhibitor PP2. We propose this altered association between membrane skeleton and membrane proteins as novel mechanism in the generation of acanthocytes in ChAc.
Krüppel-like Factor 5 contributes to pulmonary artery smooth muscle proliferation and resistance to apoptosis in human pulmonary arterial hypertension
Authors: Courboulin Audrey , Tremblay Véronique L , Barrier Marjorie , Meloche Jolyane , Jacob Maria Helena , Chapolard Mathilde , Bisserier Malik , Paulin Roxane , Lambert Caroline , Provencher Steeve , Bonnet Sébastien 
Published: September 2011

Abstract

Background
Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation of pulmonary artery smooth muscle cell (PASMC) and suppressed apoptosis. This phenotype has been associated with the upregulation of the oncoprotein survivin promoting mitochondrial membrane potential hyperpolarization (decreasing apoptosis) and the upregulation of growth factor and cytokines like PDGF, IL-6 and vasoactive agent like endothelin-1 (ET-1) promoting PASMC proliferation. Krüppel-like factor 5 (KLF5), is a zinc-finger-type transcription factor implicated in the regulation of cell differentiation, proliferation, migration and apoptosis. Recent studies have demonstrated the implication of KLF5 in tissue remodeling in cardiovascular diseases, such as atherosclerosis, restenosis, and cardiac hypertrophy. Nonetheless, the implication of KLF5 in pulmonary arterial hypertension (PAH) remains unknown. We hypothesized that KLF5 up-regulation in PAH triggers PASMC proliferation and resistance to apoptosis.

Methods and results
We showed that KFL5 is upregulated in both human lung biopsies and cultured human PASMC isolated from distal pulmonary arteries from PAH patients compared to controls. Using stimulation experiments, we demonstrated that PDGF, ET-1 and IL-6 trigger KLF-5 activation in control PASMC to a level similar to the one seen in PAH-PASMC. Inhibition of the STAT3 pathway abrogates KLF5 activation in PAH-PASMC. Once activated, KLF5 promotes cyclin B1 upregulation and promotes PASMC proliferation and triggers survivin expression hyperpolarizing mitochondria membrane potential decreasing PASMC ability to undergo apoptosis.

Conclusion
We demonstrated for the first time that KLF5 is activated in human PAH and implicated in the pro-proliferative and anti-apoptotic phenotype that characterize PAH-PASMC. We believe that our findings will open new avenues of investigation on the role of KLF5 in PAH and might lead to the identification of new therapeutic targets.