bluuebunny/crossref_metadata_2025_split huggingface dataset:
Growth-Differentiation Factor-15 Is a Robust, Independent Predictor of 11-Year Mortality Risk in Community-Dwelling Older Adults
Authors: Daniels Lori B. , Clopton Paul , Laughlin Gail A. , Maisel Alan S. , Barrett-Connor Elizabeth 
Published: May 2011

Background—
Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic marker in patients with cardiovascular disease (CVD), but its prognostic value in community-dwelling adults has not been reported. We hypothesized that GDF-15 would add incremental power for prediction of mortality in a population of community-dwelling older adults without known heart disease.

Methods and Results—

We measured plasma GDF-15, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and C-reactive protein levels in 1391 Rancho Bernardo Study participants, mean age 70 years, with no history of CVD and followed them for a mean of 11 years. In models adjusted for traditional CVD risk factors, GDF-15 was a robust predictor of all-cause, cardiovascular, and noncardiovascular mortality. GDF-15 was a stronger predictor of all-cause mortality than either NT-proBNP or C-reactive protein (hazard ratio [95% confidence interval] per SD log
10
units 1.5 [1.3 to 1.8],
P
<0.0001 for GDF-15 versus 1.3 [1.2 to 1.5],
P
<0.0001 for NT-proBNP; C-reactive protein was not a significant predictor). Among biomarkers considered, only GDF-15 predicted noncardiovascular death (hazard ratio 1.6 [1.4 to 2.0],
P
<0.0001). Growth differentiation factor-15 improved discrimination and modestly but significantly improved reclassification for all-cause and noncardiovascular mortality with borderline improvement for cardiovascular mortality; NT-proBNP significantly improved reclassification for all-cause and for cardiovascular mortality; C-reactive protein did not improve reclassification for any end point tested. Participants in the highest quartile of both GDF-15 and NT-proBNP had an increased risk of death compared with participants with only NT-proBNP elevated (hazard ratio 1.5 [1.1 to 2.0],
P
=0.01).

Conclusions—
Growth differentiation factor-15 is a strong predictor of all-cause, cardiovascular, and noncardiovascular mortality in community-dwelling older individuals, adding incremental value to traditional risk factors and to NT-proBNP and C-reactive protein levels.
Diminished metastasis in tetraspanin CD151–knockout mice
Authors: Takeda Yoshito , Li Qinglin , Kazarov Alexander R. , Epardaud Mathieu , Elpek Kutlu , Turley Shannon J. , Hemler Martin E. 
Published: May 2011

AbstractTetraspanin protein CD151 on tumor cells supports invasion and metastasis. In the present study, we show that host animal CD151 also plays a critical role. CD151-null mice showed markedly diminished experimental lung metastasis after injection of Lewis lung carcinoma or B16F10 melanoma cells. Diminished tumor cell residence in the lungs was evident 6-24 hours after injection. Consistent with an endothelial cell deficiency, isolated CD151-null mouse lung endothelial cells showed diminished support for B16F10 adhesion and transendothelial migration, diminished B16F10-induced permeability, and diminished B16F10 adhesion to extracellular matrix deposited by CD151-null mouse lung endothelial cells. However, CD151 deletion did not affect the size of metastatic foci or subcutaneous primary B16F10 tumors, tumor aggregation, tumor clearance from the blood, or tumor-induced immune cell activation and recruitment. Therefore, the effects of host CD151 on metastasis do not involve altered local tumor growth or immune surveillance. VEGF-induced endothelial cell signaling through Src and Akt was diminished in CD151-null endothelial cells. However, deficient signaling was not accompanied by reduced endothelial permeability either in vitro (monolayer permeability assay) or in vivo (VEGF-stimulated Miles assay). In summary, diminished metastasis in CD151-null host animals may be due to impaired tumor-endothelial interactions, with underlying defects in mouse lung endothelial cell extracellular matrix production.
IL-7 receptor expression identifies suicide gene–modified allospecific CD8+ T cells capable of self-renewal and differentiation into antileukemia effectors
Authors: Bondanza Attilio , Hambach Lothar , Aghai Zohara , Nijmeijer Bart , Kaneko Shin , Mastaglio Sara , Radrizzani Marina , Fleischhauer Katharina , Ciceri Fabio , Bordignon Claudio , Bonini Chiara , Goulmy Els 
Published: May 2011

Abstract
In allogeneic hematopoietic cell transplantation (HSCT), donor T lymphocytes mediate the graft-versus-leukemia (GVL) effect, but induce graft-versus-host disease (GVHD). Suicide gene therapy—that is, the genetic induction of a conditional suicide phenotype into donor T cells—allows dissociating the GVL effect from GVHD. Genetic modification with retroviral vectors after CD3 activation reduces T-cell alloreactivity. We recently found that alloreactivity is maintained when CD28 costimulation, IL-7, and IL-15 are added. Herein, we used the minor histocompatibility (mH) antigens HA-1 and H-Y as model alloantigens to directly explore the antileukemia efficacy of human T cells modified with the prototypic suicide gene herpes simplex virus thymidine kinase (tk) after activation with different stimuli. Only in the case of CD28 costimulation, IL-7, and IL-15, the repertoire of tk+ T cells contained HA-1– and H-Y–specific CD8+ cytotoxic T cells (CTL) precursors. Thymidine kinase–positive HA-1– and H-Y–specific CTLs were capable of self-renewal and differentiation into potent antileukemia effectors in vitro, and in vivo in a humanized mouse model. Self-renewal and differentiation coincided with IL-7 receptor expression. These results pave the way to the clinical investigation of T cells modified with a suicide gene after CD28 costimulation, IL-7, and IL-15 for a safe and effective GVL effect.
Autoimmunity associated with immunotherapy of cancer
Authors: Amos Sally M. , Duong Connie P. M. , Westwood Jennifer A. , Ritchie David S. , Junghans Richard P. , Darcy Phillip K. , Kershaw Michael H. 
Published: May 2011

AbstractIn this age of promise of new therapies for cancer, immunotherapy is emerging as an exciting treatment option for patients. Vaccines and cytokines are being tested extensively in clinical trials, and strategies using monoclonal antibodies and cell transfer are mediating dramatic regression of tumors in patients with certain malignancies. However, although initially advocated as being more specific for cancer and having fewer side effects than conventional therapies, it is becoming increasingly clear that many immunotherapies can lead to immune reactions against normal tissues. Immunotoxicities resulting from treatment can range from relatively minor conditions, such as skin depigmentation, to severe toxicities against crucial organ systems, such as liver, bowel, and lung. Treatment-related toxicity has correlated with better responses in some cases, and it is probable that serious adverse events from immune-mediated reactions will increase in frequency and severity as immunotherapeutic approaches become more effective. This review introduces immunotherapeutic approaches to cancer treatment, provides details of toxicities arising from therapy, and discusses future potential ways to avoid or circumvent these side effects.
Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression
Authors: Klampfl Thorsten , Harutyunyan Ashot , Berg Tiina , Gisslinger Bettina , Schalling Martin , Bagienski Klaudia , Olcaydu Damla , Passamonti Francesco , Rumi Elisa , Pietra Daniela , Jäger Roland , Pieri Lisa , Guglielmelli Paola , Iacobucci Ilaria , Martinelli Giovanni , Cazzola Mario , Vannucchi Alessandro M. , Gisslinger Heinz , Kralovics Robert 
Published: May 2011

Abstract
Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) are clonal myeloid disorders with increased production of terminally differentiated cells. The disease course is generally chronic, but some patients show disease progression (secondary myelofibrosis or accelerated phase) and/or leukemic transformation. We investigated chromosomal aberrations in 408 MPN samples using high-resolution single-nucleotide polymorphism microarrays to identify disease-associated somatic lesions. Of 408 samples, 37.5% had a wild-type karyotype and 62.5% harbored at least 1 chromosomal aberration. We identified 25 recurrent aberrations that were found in 3 or more samples. An increased number of chromosomal lesions was significantly associated with patient age, as well as with disease progression and leukemic transformation, but no association was observed with MPN subtypes, Janus kinase 2 (JAK2) mutational status, or disease duration. Aberrations of chromosomes 1q and 9p were positively associated with disease progression to secondary myelofibrosis or accelerated phase. Changes of chromosomes 1q, 7q, 5q, 6p, 7p, 19q, 22q, and 3q were positively associated with post-MPN acute myeloid leukemia. We mapped commonly affected regions to single target genes on chromosomes 3p (forkhead box P1 [FOXP1]), 4q (tet oncogene family member 2 [TET2]), 7p (IKAROS family zinc finger 1 [IKZF1]), 7q (cut-like homeobox 1 [CUX1]), 12p (ets variant 6 [ETV6]), and 21q (runt-related transcription factor 1 [RUNX1]). Our data provide insight into the genetic complexity of MPNs and implicate new genes involved in disease progression.
Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived β-glucans
Authors: Qi Chunjian , Cai Yihua , Gunn Lacey , Ding Chuanlin , Li Bing , Kloecker Goetz , Qian Keqing , Vasilakos John , Saijo Shinobu , Iwakura Yoichiro , Yannelli John R. , Yan Jun 
Published: May 2011

Abstractβ-glucans have been reported to function as a potent adjuvant to stimulate innate and adaptive immune responses. However, β-glucans from different sources are differential in their structure, conformation, and thus biologic activity. Different preparations of β-glucans, soluble versus particulate, further complicate their mechanism of action. Here we show that yeast-derived particulate β-glucan activated dendritic cells (DCs) and macrophages via a C-type lectin receptor dectin-1 pathway. Activated DCs by particulate β-glucan promoted Th1 and cytotoxic T-lymphocyte priming and differentiation in vitro. Treatment of orally administered yeast-derived particulate β-glucan elicited potent antitumor immune responses and drastically down-regulated immunosuppressive cells, leading to the delayed tumor progression. Deficiency of the dectin-1 receptor completely abrogated particulate β-glucan–mediated antitumor effects. In contrast, yeast-derived soluble β-glucan bound to DCs and macrophages independent of the dectin-1 receptor and did not activate DCs. Soluble β-glucan alone had no therapeutic effect but significantly augmented antitumor monoclonal antibody-mediated therapeutic efficacy via a complement activation pathway but independent of dectin-1 receptor. These findings reveal the importance of different preparations of β-glucans in the adjuvant therapy and allow for the rational design of immunotherapeutic protocols usable in clinical trials.
Sentinel lymph node biopsy as guidance for radical trachelectomy in young patients with early stage cervical cancer
Authors: Du Xue-lian , Sheng Xiu-gui , Jiang Tao , Li Qing-shui , Yu Hao , Pan Chun-xia , Lu Chun-hua , Wang Cong , Song Qu-qing 
Published: May 2011

Abstract

Background
The purpose of this study was to assess the feasibility and accuracy of sentinel lymph nodes (SLNs) detection using 99mTc phytate in predicting pelvic lymph nodes status for radical abdominal trachelectomy (RAT) in patients with early stage cervical cancer.

Methods
Sixty-eight women with stage IA2-IB1 cervical cancer and scheduled to undergo fertility-sparing surgery enrolled in this study. 99mTc-labeled phytate was injected before surgery. Intraoperatively, SLNs were identified, excised, and submitted to fast frozen section. Systematic bilateral pelvic lymphadenectomy and/or para-aortic lymph node dissection was performed. Then RAT was performed in patients with negative SLNs. All nodes were sent for routine pathological examination and immunostained with anti-cytokeratin antibody to detect micrometastases. Outcomes of follow up and fertility were observed.

Results
SLNs were identified in 64 of 68 patients (94.1%). Of these, SLNs of 8 patients (11.8%) were positive on frozen sections and proved to be metastasis by final pathologic examination. The sensitivity, accuracy, and false negative rates were 100%, 100%, and 0%, respectively. All 60 patients with negative SLN underwent RAT successfully. Two relapses occurred and no one died of tumor progression during follow-up. Five of the 15 patients with procreative desire conceived 8 pregnancies (3 term delivery, 2 premature birth, 1 spontaneous abortion, and 2 were still in the duration of pregnancy) after surgery.

Conclusions
The identification of SLN using 99mTc-labeled phytate is accurate and safe to assess pelvic nodes status in patients with early cervical cancer. SLNs biopsy guided RAT is feasible for patients who desire to have fertility preservation.
In vitro and in vivo assessment of the anti-malarial activity of Caesalpinia pluviosa
Authors: Kayano Ana Carolina AV , Lopes Stefanie CP , Bueno Fernanda G , Cabral Elaine C , Souza-Neiras Wanessa C , Yamauchi Lucy M , Foglio Mary A , Eberlin Marcos N , Mello João Carlos P , Costa Fabio TM 
Published: May 2011

Abstract

Background
To overcome the problem of increasing drug resistance, traditional medicines are an important source for potential new anti-malarials. Caesalpinia pluviosa, commonly named "sibipiruna", originates from Brazil and possess multiple therapeutic properties, including anti-malarial activity.

Methods
Crude extract (CE) was obtained from stem bark by purification using different solvents, resulting in seven fractions. An MTT assay was performed to evaluate cytotoxicity in MCF-7 cells. The CE and its fractions were tested in vitro against chloroquine-sensitive (3D7) and -resistant (S20) strains of Plasmodium falciparum and in vivo in Plasmodium chabaudi-infected mice. In vitro interaction with artesunate and the active C. pluviosa fractions was assessed, and mass spectrometry analyses were conducted.

Results
At non-toxic concentrations, the 100% ethanolic (F4) and 50% methanolic (F5) fractions possessed significant anti-malarial activity against both 3D7 and S20 strains. Drug interaction assays with artesunate showed a synergistic interaction with the F4. Four days of treatment with this fraction significantly inhibited parasitaemia in mice in a dose-dependent manner. Mass spectrometry analyses revealed the presence of an ion corresponding to m/z 303.0450, suggesting the presence of quercetin. However, a second set of analyses, with a quercetin standard, showed distinct ions of m/z 137 and 153.

Conclusions
The findings show that the F4 fraction of C. pluviosa exhibits anti-malarial activity in vitro at non-toxic concentrations, which was potentiated in the presence of artesunate. Moreover, this anti-malarial activity was also sustained in vivo after treatment of infected mice. Finally, mass spectrometry analyses suggest that a new compound, most likely an isomer of quercetin, is responsible for the anti-malarial activity of the F4.
Attenuating effect of pretreatment with Yiqifumai on lipopolysaccharide-induced intestine injury and survival rate in rat
Authors: Yuan Qing , Wang Jing , Fang Qiu-Hong , Liu Yu-Ying , Fan Jing-Yu , Zhang Shu-Wen , Ma Ying-Min 
Published: May 2011

Abstract

Background
Yiqifumai is a traditional Chinese medicine compound preparation used for treatment of microcirculatory disturbance-related diseases in China. We have previous reported that pretreatment with Yiqifumai could improve the lipopolysaccharide (LPS) -induced microcirculatory disturbance in rat mesentery. The present study intended to investigate the effect of pretreatment with Yiqifumai on intestine injury and survival rate of the rats subjected to LPS challenge.

Methods
Male Wistar rats were continuously infused with LPS (5 mg kg-1 body weight h-1) via the left jugular vein for 90 min. In some rats, Yiqifumai 80 (mg/kg) was administrated through the left jugular vein 10 min before LPS infusion. The mean arterial pressure (MAP), heart rate (HR), rectal temperature (RT), respiratory rate (RR) and survival rate were measured at 24 h, 48 h and 72 h after LPS infusion. At 72 h after exposure to LPS, the intestine morphology was observed under a stereomicroscope and the immunohistochemistry staining of intestine was conducted to evaluate the expression of intercellular adhesion molecule 1 (ICAM-1) and the number of myeloperoxidase (MPO) positive cells in tissue. After observation of intestine microcirculation, blood was collected from the abdominal aorta of each animal to analyze the level of inflammatory markers in plasma, including TNF-α and MCP-1.

Results
Compared to the control, LPS infusion significantly decreased MAP and the survival rate and increased the HR, RT and RR, as well as elicited leukocyte infiltration, intestine hemorrhage, enhanced expression of ICAM-1 and raised level of inflammatory markers. All of indicators, except for the RT, were significantly attenuated by Yiqifumai, in contrast to the LPS group.

Conclusions
The results demonstrated the potential of pretreatment with Yiqifumai to ameliorate rat intestine injury, inflammatory response to LPS and the decrease in survival rate caused by LPS challenge.
Is the internal rotation lag sign a sensitive test for detecting hip abductor tendon ruptures after total hip arthroplasty?
Authors: Ossendorf Christian , Bohnert Laurent , Mamisch-Saupe Nadja , Rittirsch Daniel , Wanner Guido A , Simmen Hans-Peter , Dora Claudio , Werner Clément ML 
Published: May 2011

Abstract

Introduction
Total hip arthroplasty (THA) is one of the most frequently performed procedures in orthopaedics and weakness of external rotators is often recognized thereafter. However, the etiology of lateral hip pain is multifaceted. For the diagnosis of abductor tendon rupture, magnetic resonance imaging (MRI) is the gold standard. As not every patient can be subjected to MRI, a clinical diagnostic test for easy detection of lesions of the abductor tendon is missing. Here, we present the internal rotation lack sign indicating abductor tendon pathology.

Methods
The patient is placed in lateral position on a stretcher with hips and knees in neutral position. The knee is flexed to 45° and the hip passively abducted and elevated by the investigator. With the foot passively abducted, the patient is then asked to bring his knee in direction to the examination table. This motion is also tested passively. The test is regarded positive, if no internal rotation is possible and/or if this is painful. If groin pain is elicited during either of the exercises, the test is also rated positive.

Results
We evaluated this test in 20 patients clinically and by magnetic resonance imaging (MRI). All patients demonstrated a positive internal rotation lag sign. Twelve of them lag of internal rotation and evidence of anterior abductor tendon rupture on MRI, 8 with lag of internal rotation and no evidence of abductor tendon rupture.

Conclusion
The new clinical diagnostic sign presented here may improve the diagnosis of abductor tendon rupture in the future.
Level of Evidence: Diagnostic study, level I.
CpG oligonucleotides suppress HepG2 cells-induced Jurkat cell apoptosis via the Fas-FasL-mediated pathway
Authors: Zheng Jianfeng , Fu Rongquan , Li Jing , Wang Xiaozhong 
Published: May 2011

Abstract

Objective
To explore the potential role of CpG motif-containing oligonucleotides (CpG-ODN) in modulating the expression of FasL in HepG2 and Fas in Jurkat cells in vitro, and to examine the effect of CpG-ODN treatment on the HepG2 cells-mediated Jurkat cell apoptosis in vitro.

Methods
The expressions of FasL in HepG2 and Fas in Jurkat cells were examined by real time PCR and flow cytometry (FCM). HepG2 and Jurkat cells were co-cultured, and the frequency of apoptotic Jurkat cells and levels of activated caspase-3 were determined by FCM.

Results
Treatment with CpG-ODN down-regulated the expression of FasL in HepG2 cells in a dose- and time-dependent manner. In addition, treatment with CpG-ODN down-regulated the Fas mRNA transcription and protein expression in Jurkat cells. Treatment of HepG2 cells or Jurkat cells with FasL-neutralizing antibody NOK-2 remarkably inhibited the HepG2-medaited Jurkat cell apoptosis. Pre-treatment of HepG2 or Jurkat cells with CpG-ODN significantly reduced the frequency of HepG2-mediated apoptotic Jurkat cells and inhibited the activation of caspase-3 in Jurkat cells in vitro.

Conclusions
Our data indicated that treatment with CpG-ODN inhibited the HepG2 cells-mediated Jurkat cell apoptosis by modulating the Fas/FasL pathway. Apparently, CpG-ODN treatment may be a potential therapeutic reagent for HCC.
Evaluation of Oncology Drugs at the European Medicines Agency and US Food and Drug Administration: When Differences Have an Impact on Clinical Practice
Authors: Trotta Francesco , Leufkens Hubert G.M. , Schellens Jan H.M. , Laing Richard , Tafuri Giovanni 
Published: May 2011

Purpose The aims of this study were to compare the approaches of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) in the evaluation and approval of new anticancer indications and to identify possible clinical implications associated with these differences. Methods Information on the European Union therapeutic indications for the cohort of anticancer drugs was extracted from the European Public Assessment Reports and from the FDA review reports. Results Overall, 42 anticancer drugs were approved by EMA between 1995 and 2008, corresponding to a total of 100 indications. In 47 of 100 indications, a difference was found. For 19 of these 47 indications, the difference was that one agency approved an indication, whereas the other agency did not. For the remaining 28 indications, the same indication was approved by both of the agencies and differences were evaluated through an algorithm; in 10 cases, discrepancies in therapeutic indications between EMA and FDA were considered clinically relevant. We found an overall trend that the agency that was second to give a positive approval was usually more restrictive in terms of wording of the indication compared with the agency that provided approval first. Regarding the use and robustness of available clinical data for evaluation, no clear associations could be found. Conclusion Clinically relevant differences in the outcome of the EMA and FDA approval process of oncology products were found. Neither of the agencies seems to have a prevailing restrictive behavior over the other. Further efforts on harmonizing decision making between regulatory systems are needed.