bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer Immunotherapy Using a Bispecific NK Receptor Fusion Protein that Engages both T Cells and Tumor Cells
Authors: Zhang Tong , Sentman Charles L. 
Published: February 2011

AbstractT-cell immunotherapy is a promising strategy to treat cancer, but its efficacy, complexity, and costs may pose challenges. In this study, we report the results of an investigation of a new approach to selectively activate a T-cell attack against tumor cells. The immunotherapeutic approach we developed utilizes a bifunctional fusion protein that binds tumor cells through NK (natural killer)–activating receptor NKG2D and that recruits and stimulates T cells through an anti-CD3 single-chain variable fragment (scFv-NKG2D). In vitro, this scFv-NKG2D fusion protein engaged both T cells and tumor cells, stimulating T cells to produce IFN-γ, and cytotoxicity against NKG2D ligand–positive tumor cells. In vivo, expression of scFv-NKG2D by NKG2D ligand–positive tumor cells reduced tumor burden and, in some cases, led to tumor-free survival. Administration of scFv-NKG2D in vivo also promoted survival in a murine lymphoma model. Tumor-free mice were resistant to rechallenge with cognate tumor cells, suggesting that a host-specific immunologic memory response had been generated. Host adaptive immunity including γδ T cells was required for scFv-NKG2D–mediated therapeutic efficacy. ScFv-NKG2D also inhibited the growth of NKG2D ligand–negative B16F10 tumors, reduced the percentage of myeloid-derived suppressor cells and regulatory T cells, and increased the infiltration of T cells, suggesting that scFv-NKG2D may target these immune suppressive cells. Together, these results establish scFv-NKG2D as a promising biological fusion protein to induce effective antitumor immunity. Cancer Res; 71(6); 2066–76. ©2011 AACR.
GPR54 Is a Target for Suppression of Metastasis in Endometrial Cancer
Authors: Kang Hyun Sook , Baba Tsukasa , Mandai Masaki , Matsumura Noriomi , Hamanishi Junzo , Kharma Budiman , Kondoh Eiji , Yoshioka Yumiko , Oishi Shinya , Fujii Nobutaka , Murphy Susan K. , Konishi Ikuo 
Published: February 2011

Abstract
Invasion into deep myometrium and/or lymphovascular space is a well-known risk factor for endometrial cancer metastasis, resulting in poor prognosis. It is therefore clinically important to identify novel molecules that suppress tumor invasion. Reduced expression of the metastasis suppressor, kisspeptin (KISS1), and its endogenous receptor, GPR54, has been reported in several cancers, but the significance of the KISS1/GPR54 axis in endometrial cancer metastasis has not been clarified. Metastin-10 is the minimal bioactive sequence of genetic products of KISS1. Clinicopathological analysis of 92 endometrial cancers revealed overall survival is improved in cancers with high expression of GPR54 (P &lt; 0.05) and that GPR54 expression is associated with known prognostic factors including FIGO stage, grade, and deep myometrial invasion. Through RNAi and microarray analyses, metastin-10 was predicted to suppress metastasis of GPR54-expressing endometrial cancers in vivo. Methylation analysis revealed GPR54 is epigenetically regulated. Metastin-GPR54 axis function was restored following treatment with the DNA hypomethylating agent 5-aza-DC. These data suggest that metastin-10 may be effective at inhibiting the metastatic spread of endometrial cancers in combination with demethylating agents to induce GPR54 expression. Mol Cancer Ther; 10(4); 580–90. ©2011 AACR.
Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase–Deleted Cancers
Authors: Coulthard Sally A. , Redfern Christopher P.F. , Vikingsson Svante , Lindqvist-Appell Malin , Skoglund Karin , Jakobsen-Falk Ingrid , Hall Andrew G. , Taylor Gordon A. , Hogarth Linda A. 
Published: February 2011

Abstract
The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are used in the treatment of leukemia. Incorporation of deoxythioguanosine nucleotides (dGs) into the DNA of thiopurine-treated cells causes cell death, but there is also evidence that thiopurine metabolites, particularly the 6-MP metabolite methylthioinosine monophosphate (MeTIMP), inhibit de novo purine synthesis (DNPS). The toxicity of DNPS inhibitors is influenced by methylthioadenosine phosphorylase (MTAP), a gene frequently deleted in cancers. Because the growth of MTAP-deleted tumor cells is dependent on DNPS or hypoxanthine salvage, we would predict such cells to show differential sensitivity to 6-MP and 6-TG. To test this hypothesis, sensitivity to 6-MP and 6-TG was compared in relation to MTAP status using cytotoxicity assays in two MTAP-deficient cell lines transfected to express MTAP: the T-cell acute lymphoblastic leukemic cell line, Jurkat, transfected with MTAP cDNA under the control of a tetracycline-inducible promoter, and a lung cancer cell line (A549-MTAP−) transfected to express MTAP constitutively (A549-MTAP+). Sensitivity to 6-MP or methyl mercaptopurine riboside, which is converted intracellularly to MeTIMP, was markedly higher in both cell lines under MTAP− conditions. Measurement of thiopurine metabolites support the hypothesis that DNPS inhibition is a major cause of cell death with 6-MP, whereas dGs incorporation is the main cause of cytotoxicity with 6-TG. These data suggest that thiopurines, particularly 6-MP, may be more effective in patients with deleted MTAP. Mol Cancer Ther; 10(3); 495–504. ©2011 AACR.
Lipoprotein Lipase Links Dietary Fat to Solid Tumor Cell Proliferation
Authors: Kuemmerle Nancy B. , Rysman Evelien , Lombardo Portia S. , Flanagan Alison J. , Lipe Brea C. , Wells Wendy A. , Pettus Jason R. , Froehlich Heather M. , Memoli Vincent A. , Morganelli Peter M. , Swinnen Johannes V. , Timmerman Luika A. , Chaychi Leila , Fricano Catherine J. , Eisenberg Burton L. , Coleman William B. , Kinlaw William B. 
Published: February 2011

Abstract
Many types of cancer cells require a supply of fatty acids (FA) for growth and survival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We hypothesized that, in addition to synthesis, cancer cells may obtain preformed, diet-derived FA by uptake from the bloodstream. This would require hydrolytic release of FA from triglyceride in circulating lipoprotein particles by the secreted enzyme lipoprotein lipase (LPL), and the expression of CD36, the channel for cellular FA uptake. We find that selected breast cancer and sarcoma cells express and secrete active LPL, and all express CD36. We further show that LPL, in the presence of triglyceride-rich lipoproteins, accelerates the growth of these cells. Providing LPL to prostate cancer cells, which express low levels of the enzyme, did not augment growth, but did prevent the cytotoxic effect of FA synthesis inhibition. Moreover, LPL knockdown inhibited HeLa cell growth. In contrast to the cell lines, immunohistochemical analysis confirmed the presence of LPL and CD36 in the majority of breast, liposarcoma, and prostate tumor tissues examined (n = 181). These findings suggest that, in addition to de novo lipogenesis, cancer cells can use LPL and CD36 to acquire FA from the circulation by lipolysis, and this can fuel their growth. Interfering with dietary fat intake, lipolysis, and/or FA uptake will be necessary to target the requirement of cancer cells for FA. Mol Cancer Ther; 10(3); 427–36. ©2011 AACR.
Targeting Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase 2 by Curcumin Induces ER Stress-Associated Apoptosis for Treating Human Liposarcoma
Authors: Wang Lu , Wang Lingxian , Song Ran , Shen Yan , Sun Yang , Gu Yanhong , Shu Yongqian , Xu Qiang 
Published: February 2011

Abstract
Human liposarcoma is the most common soft tissue sarcoma. There is no effective therapy so far except for surgery. In this study, we report for the first time that curcumin induces endoplasmic reticulum (ER) stress in human liposarcoma cells via interacting with sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2). Curcumin dose-dependently inhibited the cell survival of human liposarcoma cell line SW872 cells, but did not affect that of human normal adipose-derived cells. Curcumin-mediated ER stress via inhibiting the activity of SERCA2 caused increasing expressions of CHOP and its transcription target death receptor 5 (TRAIL-R2), leading to a caspase-3 and caspase-8 cascade-dependent apoptosis in SW872 cells in vitro and in vivo. Moreover, 70% of human liposarcoma tissues showed an elevated SERCA2 expression compared with normal adipose tissues. Curcumin dose-dependently inhibited the activity of SERCA2, and the interaction of molecular docking and colocalization in ER of curcumin with SERCA2 were further observed. These findings suggest that curcumin may serve as a potent agent for curing human liposarcoma via targeting SERCA2. Mol Cancer Ther; 10(3); 461–71. ©2011 AACR.
Heritability of Early Repolarization
Authors: Reinhard Wibke , Kaess Bernhard M. , Debiec Radoslaw , Nelson Christopher P. , Stark Klaus , Tobin Martin D. , Macfarlane Peter W. , Tomaszewski Maciej , Samani Nilesh J. , Hengstenberg Christian 
Published: February 2011

Background—
Early repolarization (ER), defined by J-point elevation in 12-lead ECG, was recently associated with increased risk for idiopathic ventricular fibrillation and cardiovascular mortality. The determinants of ER are unknown. We investigated its heritability in a large, family-based cohort.

Methods and Results—

The study sample comprised 1877 individuals from 505 white nuclear families representative of the British general population. Standard 12-lead ECGs were evaluated for the presence of ER, defined as J-point elevation of ≥0.1 mV in at least 2 adjacent inferior (II, III, and aVF) or anterolateral (I, aVL, and V
4
through V
6
) leads. Narrow sense heritability estimates were computed adjusting for age, age
2
, and sex. The prevalence of ER was 7.7% (n=145) in the whole cohort, 5.9% (n=56) in parents, and 9.6% (n=89) in offspring. Heritability estimate for the presence of ER was calculated at h
2
=0.49 (standard error=0.14;
P
=2.7*10
−4
) and was higher when restricted to its presence in inferior leads (h
2
=0.61, standard error=0.18,
P
=4.3*10
−4
) or for the notching ER morphology (h
2
=0.81, standard error=0.19,
P
=2.4*10
−5
). Individuals with at least 1 affected parent had a 2.5-fold increased risk for presenting with ER on ECG (odds ratio, 2.54; 95% confidence interval, 1.33 to 4.84;
P
=0.005). Familial transmission was more frequent when the mother was affected (odds ratio, 3.84; 95% confidence interval, 1.41 to 10.43;
P
=0.008) than when the father was affected (odds ratio, 1.82; 95% confidence interval, 0.82 to 4.03;
P
=0.141), although this difference was not statistically significant (
P
=0.18).

Conclusions—
ER is a heritable phenotype. Offspring of ER-positive parents have a 2.5-fold increased risk of presenting with ER on their ECG.
Inhaled Nitrite Reverses Hemolysis-Induced Pulmonary Vasoconstriction in Newborn Lambs Without Blood Participation
Authors: Blood Arlin B. , Schroeder Hobe J. , Terry Michael H. , Merrill-Henry Jeanette , Bragg Shannon L. , Vrancken Kurt , Liu Taiming , Herring Jason L. , Sowers Lawrence C. , Wilson Sean M. , Power Gordon G. 
Published: February 2011

Background—
Nitrite can be converted to nitric oxide (NO) by a number of different biochemical pathways. In newborn lambs, an aerosol of inhaled nitrite has been found to reduce pulmonary blood pressure, possibly acting via conversion to NO by reaction with intraerythrocytic deoxyhemoglobin. If so, the vasodilating effects of nitrite would be attenuated by free hemoglobin in plasma that would rapidly scavenge NO.

Methods and Results—

Pulmonary vascular pressures and resistances to flow were measured in anesthetized newborn lambs. Plasma hemoglobin concentrations were then elevated, resulting in marked pulmonary hypertension. This effect was attenuated if infused hemoglobin was first oxidized to methemoglobin, which does not scavenge NO. These results further implicate NO as a tonic pulmonary vasodilator. Next, while free hemoglobin continued to be infused, the lambs were given inhaled NO gas (20 ppm), inhaled sodium nitrite aerosol (0.87 mol/L), or an intravascular nitrite infusion (3 mg/h bolus, 5 mg · kg
−1
· h
−1
infusion). Inhaled NO and inhaled nitrite aerosol both resulted in pulmonary vasodilation. Intravascular infusion of nitrite, however, did not. Increases in exhaled NO gas were observed in lambs while breathing the nitrite aerosol (≈20 ppb NO) but not during intravascular infusion of nitrite.

Conclusions—
We conclude that the pulmonary vasodilating effect of inhaled nitrite results from its conversion to NO in airway and parenchymal lung tissue and is not dependent on reactions with deoxyhemoglobin in the pulmonary circulation. Inhaled nitrite aerosol remains a promising candidate to reduce pulmonary hypertension in clinical application.
Growth Factor Therapy and Autologous Lymph Node Transfer in Lymphedema
Authors: Lähteenvuo Markku , Honkonen Krista , Tervala Tomi , Tammela Tuomas , Suominen Erkki , Lähteenvuo Johanna , Kholová Ivana , Alitalo Kari , Ylä-Herttuala Seppo , Saaristo Anne 
Published: February 2011

Background—
Lymphedema after surgery, infection, or radiation therapy is a common and often incurable problem. Application of lymphangiogenic growth factors has been shown to induce lymphangiogenesis and to reduce tissue edema. The therapeutic effect of autologous lymph node transfer combined with adenoviral growth factor expression was evaluated in a newly established porcine model of limb lymphedema.

Methods and Results—
The lymphatic vasculature was destroyed within a 3-cm radius around an inguinal lymph node. Lymph node grafts and adenovirally (Ad) delivered vascular endothelial growth factor (VEGF)-C (n=5) or VEGF-D (n=9) were used to reconstruct the lymphatic network in the inguinal area; AdLacZ (β-galactosidase; n=5) served as a control. Both growth factors induced robust growth of new lymphatic vessels in the defect area, and postoperative lymphatic drainage was significantly improved in the VEGF-C/D–treated pigs compared with controls. The structure of the transferred lymph nodes was best preserved in the VEGF-C–treated pigs. Interestingly, VEGF-D transiently increased accumulation of seroma fluid in the operated inguinal region postoperatively, whereas VEGF-C did not have this side effect.

Conclusions—
These results show that growth factor gene therapy coupled with lymph node transfer can be used to repair damaged lymphatic networks in a large animal model and provide a basis for future clinical trials of the treatment of lymphedema.
Microsomal Prostaglandin E
2
Synthase-1 Modulates the Response to Vascular Injury
Authors: Wang Miao , Ihida-Stansbury Kaori , Kothapalli Devashish , Tamby Mathieu C. , Yu Zhou , Chen Lihong , Grant Gregory , Cheng Yan , Lawson John A. , Assoian Richard K. , Jones Peter L. , FitzGerald Garret A. 
Published: February 2011

Background—

Microsomal (m) prostaglandin (PG) E
2
synthase (S)-1 catalyzes the formation of PGE
2
from PGH
2
, a cyclooxygenase product that is derived from arachidonic acid. Previous studies in mice suggest that targeting mPGES-1 may be less likely to cause hypertension or thrombosis than cyclooxygenase-2–selective inhibition or deletion in vivo. Indeed, deletion of mPGES-1 retards atherogenesis and angiotensin II–induced aortic aneurysm formation. The role of mPGES-1 in the response to vascular injury is unknown.

Methods and Results—

Mice were subjected to wire injury of the femoral artery. Both neointimal area and vascular stenosis were significantly reduced 4 weeks after injury in mPGES-1 knockout mice compared with wild-type controls (65.6±5.7 versus 37.7±5.1×10
3
pixel area and 70.5±13.4% versus 47.7±17.4%, respectively;
P
<0.01). Induction of tenascin-C, a proproliferative and promigratory extracellular matrix protein, after injury was attenuated in the knockouts. Consistent with in vivo rediversion of PG biosynthesis, mPGES-1–deleted vascular smooth muscle cells generated less PGE
2
but more PGI
2
and expressed reduced tenascin-C compared with wild-type cells. Both suppression of PGE
2
and augmentation of PGI
2
attenuate tenascin-C expression and vascular smooth muscle cell proliferation and migration in vitro.

Conclusions—
Deletion of mPGES-1 in mice attenuates neointimal hyperplasia after vascular injury, in part by regulating tenascin-C expression. This raises for consideration the therapeutic potential of mPGES-1 inhibitors as adjuvant therapy for percutaneous coronary intervention.
Inflammasome Activation of Cardiac Fibroblasts Is Essential for Myocardial Ischemia/Reperfusion Injury
Authors: Kawaguchi Masanori , Takahashi Masafumi , Hata Takeki , Kashima Yuichiro , Usui Fumitake , Morimoto Hajime , Izawa Atsushi , Takahashi Yasuko , Masumoto Junya , Koyama Jun , Hongo Minoru , Noda Tetsuo , Nakayama Jun , Sagara Junji , Taniguchi Shun'ichiro , Ikeda Uichi 
Published: February 2011

Background—
Inflammation plays a key role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury; however, the mechanism by which myocardial I/R induces inflammation remains unclear. Recent evidence indicates that a sterile inflammatory response triggered by tissue damage is mediated through a multiple-protein complex called the inflammasome. Therefore, we hypothesized that the inflammasome is an initial sensor for danger signal(s) in myocardial I/R injury.

Methods and Results—
We demonstrate that inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, is crucially involved in the initial inflammatory response after myocardial I/R injury. We found that inflammasomes are formed by I/R and that its subsequent activation of inflammasomes leads to interleukin-1β production, resulting in inflammatory responses such as inflammatory cell infiltration and cytokine expression in the heart. In mice deficient for apoptosis-associated speck-like adaptor protein and caspase-1, these inflammatory responses and subsequent injuries, including infarct development and myocardial fibrosis and dysfunction, were markedly diminished. Bone marrow transplantation experiments with apoptosis-associated speck-like adaptor protein–deficient mice revealed that inflammasome activation in bone marrow cells and myocardial resident cells such as cardiomyocytes or cardiac fibroblasts plays an important role in myocardial I/R injury. In vitro experiments revealed that hypoxia/reoxygenation stimulated inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, and that hypoxia/reoxygenation–induced activation was mediated through reactive oxygen species production and potassium efflux.

Conclusions—
Our results demonstrate the molecular basis for the initial inflammatory response after I/R and suggest that the inflammasome is a potential novel therapeutic target for preventing myocardial I/R injury.
Use of Tutoplast‐Processed Fascia Lata as an Onlay Graft Material for Tip Surgery in Rhinoplasty
Authors: Jang Yong Ju , Kim Ji Heui 
Published: February 2011

ObjectivesTutoplast‐processed fascia lata (TPFL) is a commercially available homograft that has been successfully used as human graft tissue for dorsal augmentation in rhinoplasty. The present study evaluated the use of TPFL as an onlay tip graft material in rhinoplasty.Study DesignCase series with chart review.SettingAcademic tertiary care medical center.Subjects and MethodsThe study involved a retrospective analysis of rhinoplasty cases using TPFL as a tip onlay graft. The study included 82 patients (46 men and 36 women) who underwent tip surgery using TPFL from February 2006 to June 2008. By comparing facial photographs before and after the operation, 2 independent rhinoplastic surgeons assessed outcomes of 8 months postoperative time as being excellent, fair, or poor. Using the pre‐ and postoperative profile view, anthropometric measurements were also made.ResultsThe 82 subjects included 71 primary and 11 revision patients. TPFL was used as a tip onlay graft in final tip modification. Postoperative assessment found that only 6 (7%) patients had excellent results, 51 (62%) had fair results, and 25 (31%) had poor results. Pre‐ and postoperative anthropometric measurements showed the technique resulted in an overall increased nasal tip projection postoperatively (0.56 ± 0.09 vs 0.60 ± 0.08; P <. 05). However, the overall nasolabial angle was not changed after surgery (91.35 ± 10.36° vs 93.05 ± 8.3°; P =. 08). No patient experienced infection, visible graft contour, or migration.ConclusionTPFL was not that satisfactory in terms of aesthetic outcome when used as a tip onlay graft material in rhinoplasty patients.
Power Relations and Economic Paradigms, or Why Post-Keynesian Theory Is Not Dominant
Authors: Reati Angelo 
Published: February 2011

In spite of its substantial results in understanding modern capitalism and the fact that, until the 1970s, Keynesian theory inspired the economic policy of most countries, the classical/post-Keynesian paradigm failed to become dominant on the theoretical scene. Why? Pasinetti’s book provides an answer by first pointing out the “unwise behavior” of the Cambridge group of Keynesian scholars, then by suggesting how to overcome the present theoretical impasse by the methodological device of the “separation theorem.” Economic enquiry, he argues, should distinguish the phase of “pure theory,” to be elaborated at a logical stage that precedes institutions, from the (applied) institutional analysis. The review concludes by maintaining that, while Pasinetti’s suggestion is fully valid, the theoretical strength of a paradigm is a necessary but not sufficient condition for becoming dominant. As the last decades show, the success or failure of a paradigm is also crucially dependent on social and power relations in society. JEL classification: B50; B31; E12