bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Complexity and AKT Dependence in Serous Ovarian Cancer
Authors: Hanrahan Aphrothiti J. , Schultz Nikolaus , Westfal Maggie L. , Sakr Rita A. , Giri Dilip D. , Scarperi Stefano , Janikariman Manickam , Olvera Narciso , Stevens Ellen V. , She Qing-Bai , Aghajanian Carol , King Tari A. , de Stanchina Elisa , Spriggs David R. , Heguy Adriana , Taylor Barry S. , Sander Chris , Rosen Neal , Levine Douglas A. , Solit David B. 
Published: November 2011

Abstract
Effective oncoprotein-targeted therapies have not yet been developed for ovarian cancer. To explore the role of phosphatidylinositol 3-kinase (PI3K)/AKT signaling in this disease, we performed a genetic and functional analysis of ovarian cancer cell lines and tumors. PI3K pathway alterations were common in both, but the spectrum of mutational changes differed. Genetic activation of the pathway was necessary, but not sufficient, to confer sensitivity to selective inhibition of AKT and cells with RAS pathway alterations or RB1 loss were resistant to AKT inhibition, whether or not they had coexistent PI3K/AKT pathway activation. Inhibition of AKT1 caused growth arrest in a subset of ovarian cell lines, but not in those with AKT3 expression, which required pan-AKT inhibition. Thus, a subset of ovarian tumors is sensitive to AKT inhibition, but the genetic heterogeneity of the disease suggests that effective treatment with AKT pathway inhibitors will require a detailed molecular analysis of each patient's tumor.
Significance: A subset of ovarian cancers exhibits AKT pathway activation and is sensitive to selective AKT inhibition. Ovarian tumors exhibit significant genetic heterogeneity and thus an individualized approach based on real-time, detailed genomic and proteomic characterization of individual tumors will be required for the successful application of PI3K/AKT pathway inhibitors in this disease. Cancer Discovery; 2(1); 56–67. ©2011 AACR.
Read the Commentary on this article by Bast and Mills, p. 16
This article is highlighted in the In This Issue feature, p. 1
Reperfusion Injury Intensifies the Adaptive Human T Cell Alloresponse in a Human-Mouse Chimeric Artery Model
Authors: Yi Tai , Fogal Birgit , Hao Zhengrong , Tobiasova Zuzana , Wang Chen , Rao Deepak A. , Al-Lamki Rafia S. , Kirkiles-Smith Nancy C. , Kulkarni Sanjay , Bradley John R. , Bothwell Alfred L.M. , Sessa William C. , Tellides George , Pober Jordan S. 
Published: November 2011

Objective—
Perioperative nonimmune injuries to an allograft can decrease graft survival. We have developed a model for studying this process using human materials.

Methods and Results—
Human artery segments were transplanted as infrarenal aortic interposition grafts into an immunodeficient mouse host, allowed to “heal in” for 30 days, and then retransplanted into a second mouse host. To induce a reperfusion injury, the healed-in artery segments were incubated for 3 hours under hypoxic conditions ex vivo before retransplantation. To induce immunologic rejection, the animals receiving the retransplanted artery segment were adoptively transferred with human peripheral blood mononuclear cells or purified T cells from a donor allogeneic to the artery 1 week before surgery. To compare rejection of injured versus healthy tissues, these manipulations were combined. Results were analyzed ex vivo by histology, morphometry, immunohistochemistry, and mRNA quantitation or in vivo by ultrasound. Our results showed that reperfusion injury, which otherwise heals with minimal sequelae, intensifies the degree of allogeneic T cell–mediated injury to human artery segments.

Conclusion—
We developed a new human-mouse chimeric model demonstrating interactions of reperfusion injury and alloimmunity using human cells and tissues that may be adapted to study other forms of nonimmune injury and other types of adaptive immune responses.
Neuroprotective Effect of Acute Ethanol Administration in a Rat With Transient Cerebral Ischemia
Authors: Wang Fei , Wang Yu , Geng Xiaokun , Asmaro Karam , Peng Changya , Sullivan Jonathon M. , Ding Jamie Y. , Ji Xunming , Ding Yuchuan 
Published: November 2011

Background and Purpose—
Ethanol consumption is inversely associated with the risk of ischemic stroke, suggesting a neuroprotective effect. In a rat model of transient cerebral ischemia, we identified ethanol as a possible treatment for acute ischemic stroke.

Methods—
Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 2 hours. Five sets of experiments were conducted: to determine the dose–response effect of ethanol on brain infarction and functional outcome; to determine whether combining ethanol and hypothermia produces synergistic neuroprotection; to determine the therapeutic windows of opportunity for ethanol in stroke; to test whether ethanol promotes intracerebral hemorrhage in a hemorrhagic or ischemic stroke or after administration of thrombolytics; and to test the affect of ethanol on hypoxia-inducible factor-1α protein expression.

Results—
Ethanol at 1.5 g/kg reduced infarct volume and behavioral dysfunction when administered at 2, 3, or 4 hours after middle cerebral artery occlusion. The protective effect of ethanol was not improved when paired with hypothermia. Ethanol did not promote cerebral hemorrhage in hemorrhagic or ischemic stroke in combination with recombinant tissue-type plasminogen activator or urokinase. Ethanol treatment (1.5 g/kg) increased protein levels of hypoxia-inducible factor-1α at 3 hours postreperfusion.

Conclusions—
Ethanol exerts a strong neuroprotective effect when administered up to 4 hours after ischemia, increases expression of hypoxia-inducible factor-1α, and does not promote intracerebral hemorrhage when used with thrombolytics. Ethanol is a potential neuroprotectant for acute ischemic stroke.
A Rat Model of Studying Tissue-Type Plasminogen Activator Thrombolysis in Ischemic Stroke With Diabetes
Authors: Fan Xiang , Qiu Jianhua , Yu Zhanyang , Dai Haibin , Singhal Aneesh B. , Lo Eng H. , Wang Xiaoying 
Published: November 2011

Background and Purpose—
Poststroke hyperglycemia and diabetes mellitus are associated with lower thrombolytic efficacy and an increased risk of postischemic cerebral hemorrhage. We aimed to develop a rodent model of thrombolysis in diabetic stroke that mimics the clinical situation.

Method—
Male 6-week Type I diabetic rats (14 weeks old) were subjected to embolic focal stroke and treated with tissue-type plasminogen activator at 1.5 hours. Reperfusion and 24-hour neurological outcomes were measured and compared with nondiabetic control rats.

Results—
Diabetic rats exhibited resistance to thrombolytic reperfusion, larger infarction volumes, and increased intracerebral hemorrhage.

Conclusions—
This animal model would be relevant to future studies investigating pathophysiological mechanisms and in developing new therapeutic approaches to enhance the efficacy of tissue-type plasminogen activator thrombolysis in stroke patients with diabetes or poststroke hyperglycemia.
Protective Effect of Erdosteine against Cisplatin‐Induced Ototoxicity in a Guinea Pig Model
Authors: Waissbluth Sofia , Dupuis Isabelle , Daniel Sam J. 
Published: November 2011

ObjectiveCisplatin is a commonly used chemotherapeutic agent. One of its major dose‐limiting side effects is ototoxicity. No treatment has yet been approved for this condition. The objective of this study was to determine the potential protective effect of a systemic administration of erdosteine against cisplatin‐induced ototoxicity.Study DesignA prospective controlled trial conducted in an animal model.SettingAnimal care research facilities of The Montreal Children’s Hospital Research Institute.Subjects and MethodsA total of 27 guinea pigs were assigned to 4 groups, each receiving a different concentration of intraperitoneal erdosteine: group 1 (control group; n = 9) did not receive erdosteine, group 2 (n = 6) received 100 mg/kg/d, group 3 (n = 6) received 200 mg/kg/d, and group 4 (n = 6) received 500 mg/kg/d. The animals in the experimental groups received the erdosteine injection daily for 4 days. All of the animals received 12 mg/kg of intraperitoneal cisplatin. Auditory brainstem response threshold shifts were measured at 4 frequencies (8, 16, 20, and 25 kHz) for all groups. Scanning electron microscopy and outer hair cell counts were performed to assess the protective effect of erdosteine.ResultsSignificant protection was observed in groups 3 and 4 at 25 kHz. These findings are supported by outer hair cell counts by scanning electron microscopy.ConclusionA systemic administration of erdosteine appears to provide an otoprotective effect at high frequencies for cisplatin‐induced ototoxicity.
Rosiglitazone Causes Endothelial Dysfunction in Humans
Authors: Perampaladas Kumar , Gori Tommaso , Parker John D. 
Published: November 2011

Objectives: We explored the impact of rosiglitazone on endothelial function in normal volunteers and its interaction with glyceryl trinitrate (GTN)-induced abnormalities in endothelial function. We hypothesized that rosiglitazone would have a neutral effect on endothelial function in normal volunteers and would favorably modify endothelial dysfunction induced by GTN. Methods: In this double-blind, randomized, placebo-controlled study, 44 participants were randomized to placebo, rosiglitazone (4 mg twice daily), transdermal GTN (0.6 mg/h), or both GTN and rosiglitazone. After 7 days of treatment, participants underwent measures of forearm blood flow during brachial artery infusion of acetylcholine (Ach). Serum glucose concentrations and insulin sensitivity were assessed. Results: Unexpectedly, rosiglitazone-treated participants experienced blunted responses to endothelium-dependent responses to Ach ( P < .05 vs placebo). Sustained GTN administration caused similar abnormalities in endothelial function ( P < .05 vs placebo) and rosiglitazone + GTN ( P < .05 vs placebo; P = ns vs rosiglitazone). Interestingly, co-infusion of the antioxidant vitamin C improved endothelial responses in those randomized to rosiglitazone and GTN alone ( P = not significant [ns] compared with placebo), but it did not improve endothelial function in those treated with rosiglitazone + GTN. Neither rosiglitazone nor GTN treatment modified the measures of glucose metabolism. Conclusions: Unexpectedly, therapy with rosiglitazone caused abnormalities in endothelial function in normal volunteers. These findings have important implications with respect to drug development and surveillance.
Protumoral role of monocytes in human B-cell precursor acute lymphoblastic leukemia: involvement of the chemokine CXCL10
Authors: Lee Yunqin , Chittezhath Manesh , André Valentina , Zhao Helen , Poidinger Michael , Biondi Andrea , D'Amico Giovanna , Biswas Subhra K. 
Published: November 2011

Abstract
Myelomonocytic cells play a key role in the progression of many solid tumors. However, very little is known about their contribution to the progression of hematopoietic cancers. We investigated the role of monocytes in the progression of human B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We demonstrated that coculturing human monocytes in vitro with CD19+ BCP-ALL blasts from patients “conditioned” them to an inflammatory phenotype characterized by significant up-regulation of the chemokine, CXCL10. This phenotype was also observable ex vivo in monocytes isolated from BCP-ALL patients, which show elevated CXCL10 production compared with monocytes from healthy donors. Functionally, the “conditioned” monocytes promoted migration and invasive capacity of BCP-ALL cells. Increased invasion was mediated by matrix metalloproteinase 9 expression and activity in the BCP-ALL cells induced by the monocyte-derived CXCL10. However, neither the “conditioned” monocytes nor the CXCL10 produced by these cells had any effect on the proliferation/viability of BCP-ALL cells and angiogenesis. Collectively, our results strongly suggest a protumoral role for human monocytes in BCP-ALL, orchestrated by CXCL10 and its effect on tumor cell migration and invasion. These observations highlight the importance of the CXCL10/CXCR3 chemokine circuit in BCP-ALL progression.
Long-term prognosis of symptomatic isolated middle cerebral artery disease in Korean stroke patients
Authors: Oh Mi Sun , Yu Kyung-Ho , Chu Min-Kyung , Ma Hyeo-Il , Kim Yun Joong , Kim Joo Yong , Lee Byung-Chul 
Published: November 2011

Abstract

Background
This study aimed to investigate the long-term mortality and recurrence rate of stroke in first-time stroke patients with symptomatic isolated middle cerebral artery disease (MCAD) under medical management.

Methods
We identified 141 first ever stroke patients (mean age, 64.4 ± 12.5 years; 53% male) with symptomatic isolated MCAD. MCAD was defined as significant stenosis of more than 50% or occlusion of the MCA as revealed by MR angiography. The median follow-up was 27.7 months. We determined a cumulative rate of stroke recurrence and mortality by Kaplan-Meier survival analyses and sought predictors using the Cox proportional hazard model.

Results
The cumulative composite outcome rate (stroke recurrence or any-cause death) was 14%, 19%, 22%, and 28% at years 1, 2, 3, and 5, respectively. The annual recurrence rate of stroke was 4.1%. The presence of diabetes mellitus was the only significant independent predictor of stroke recurrence or any cause of death in multivariate analyses of Cox proportional hazard model adjusted for any plausible potential confounding factors.

Conclusions
We estimated the long-term prognosis of stroke patients with isolated symptomatic MCAD under current medical management in Korea. Diabetes mellitus was found to be a significant predictor for stroke recurrence and mortality.
Deciphering causal and statistical relations of molecular aberrations and gene expressions in NCI-60 cell lines
Authors: Li Shyh-Dar , Tagami Tatsuaki , Ho Ying-Fu , Yeang Chen-Hsiang 
Published: November 2011

Abstract

Background
Cancer cells harbor a large number of molecular alterations such as mutations, amplifications and deletions on DNA sequences and epigenetic changes on DNA methylations. These aberrations may dysregulate gene expressions, which in turn drive the malignancy of tumors. Deciphering the causal and statistical relations of molecular aberrations and gene expressions is critical for understanding the molecular mechanisms of clinical phenotypes.

Results
In this work, we proposed a computational method to reconstruct association modules containing driver aberrations, passenger mRNA or microRNA expressions, and putative regulators that mediate the effects from drivers to passengers. By applying the module-finding algorithm to the integrated datasets of NCI-60 cancer cell lines, we found that gene expressions were driven by diverse molecular aberrations including chromosomal segments' copy number variations, gene mutations and DNA methylations, microRNA expressions, and the expressions of transcription factors. In-silico validation indicated that passenger genes were enriched with the regulator binding motifs, functional categories or pathways where the drivers were involved, and co-citations with the driver/regulator genes. Moreover, 6 of 11 predicted MYB targets were down-regulated in an MYB-siRNA treated leukemia cell line. In addition, microRNA expressions were driven by distinct mechanisms from mRNA expressions.

Conclusions
The results provide rich mechanistic information regarding molecular aberrations and gene expressions in cancer genomes. This kind of integrative analysis will become an important tool for the diagnosis and treatment of cancer in the era of personalized medicine.
Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture
Authors: Lahti Anna L. , Kujala Ville J. , Chapman Hugh , Koivisto Ari-Pekka , Pekkanen-Mattila Mari , Kerkelä Erja , Hyttinen Jari , Kontula Kimmo , Swan Heikki , Conklin Bruce R. , Yamanaka Shinya , Silvennoinen Olli , Aalto-Setälä Katriina 
Published: November 2011

SUMMARY
Long QT syndrome (LQTS) is caused by functional alterations in cardiac ion channels and is associated with prolonged cardiac repolarization time and increased risk of ventricular arrhythmias. Inherited type 2 LQTS (LQT2) and drug-induced LQTS both result from altered function of the hERG channel. We investigated whether the electrophysiological characteristics of LQT2 can be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology. Spontaneously beating cardiomyocytes were differentiated from two iPSC lines derived from an individual with LQT2 carrying the R176W mutation in the KCNH2 (HERG) gene. The individual had been asymptomatic except for occasional palpitations, but his sister and father had died suddenly at an early age. Electrophysiological properties of LQT2-specific cardiomyocytes were studied using microelectrode array and patch-clamp, and were compared with those of cardiomyocytes derived from control cells. The action potential duration of LQT2-specific cardiomyocytes was significantly longer than that of control cardiomyocytes, and the rapid delayed potassium channel (IKr) density of the LQT2 cardiomyocytes was significantly reduced. Additionally, LQT2-derived cardiac cells were more sensitive than controls to potentially arrhythmogenic drugs, including sotalol, and demonstrated arrhythmogenic electrical activity. Consistent with clinical observations, the LQT2 cardiomyocytes demonstrated a more pronounced inverse correlation between the beating rate and repolarization time compared with control cells. Prolonged action potential is present in LQT2-specific cardiomyocytes derived from a mutation carrier and arrhythmias can be triggered by a commonly used drug. Thus, the iPSC-derived, disease-specific cardiomyocytes could serve as an important platform to study pathophysiological mechanisms and drug sensitivity in LQT2.
The use of CRP within a clinical prediction algorithm for the differentiation of septic arthritis and transient synovitis in children
Authors: Singhal R. , Perry D. C. , Khan F. N. , Cohen D. , Stevenson H. L. , James L. A. , Sampath J. S. , Bruce C. E. 
Published: November 2011

Clinical prediction algorithms are used to differentiate transient synovitis from septic arthritis. These algorithms typically include the erythrocyte sedimentation rate (ESR), although in clinical practice measurement of the C-reactive protein (CRP) has largely replaced the ESR. We evaluated the use of CRP in a predictive algorithm. The records of 311 children with an effusion of the hip, which was confirmed on ultrasound, were reviewed (mean age 5.3 years (0.2 to 15.1)). Of these, 269 resolved without intervention and without long-term sequelae and were considered to have had transient synovitis. The remaining 42 underwent arthrotomy because of suspicion of septic arthritis. Infection was confirmed in 29 (18 had micro-organisms isolated and 11 had a high synovial fluid white cell count). In the remaining 13 no evidence of infection was found and they were also considered to have had transient synovitis. In total 29 hips were categorised as septic arthritis and 282 as transient synovitis. The temperature, weight-bearing status, peripheral white blood cell count and CRP was reviewed in each patient. A CRP > 20 mg/l was the strongest independent risk factor for septic arthritis (odds ratio 81.9, p < 0.001). A multivariable prediction model revealed that only two determinants (weight-bearing status and CRP > 20 mg/l) were independent in differentiating septic arthritis from transient synovitis. Individuals with neither predictor had a < 1% probability of septic arthritis, but those with both had a 74% probability of septic arthritis. A two-variable algorithm can therefore quantify the risk of septic arthritis, and is an excellent negative predictor.
Effect of intra-articular lesions on the outcome of periacetabular osteotomy in patients with symptomatic hip dysplasia
Authors: Fujii M. , Nakashima Y. , Yamamoto T. , Mawatari T. , Motomura G. , Iwamoto Y. , Noguchi Y. 
Published: November 2011

In order to clarify how intra-articular lesions influence the survival of a periacetabular osteotomy in patients with dysplasia of the hip, we performed an observational study of 121 patients (121 hips) who underwent a transposition osteotomy of the acetabulum combined with an arthroscopy. Their mean age was 40.2 years (13 to 64) and the mean follow-up was 9.9 years (2 to 18). Labral and cartilage degeneration tended to originate from the anterosuperior part of the acetabulum, followed by the femoral side. In all, eight hips (6.6%) had post-operative progression to Kellgren–Lawrence grade 4 changes, and these hips were associated with the following factors: moderate osteoarthritis, decreased width of the joint space, joint incongruity, and advanced intra-articular lesions (subchondral bone exposure in the cartilage and a full-thickness labral tear). Multivariate analysis indicated subchondral bone exposure on the femoral head as an independent risk factor for progression of osteoarthritis (p = 0.003). In hips with early stage osteoarthritis, femoral subchondral bone exposure was a risk factor for progression of the grade of osteoarthritis.Although the outcome of transposition osteotomy of the acetabulum was satisfactory, post-operative progression of osteoarthritis occurred at a high rate in hips with advanced intra-articular lesions, particularly in those where the degenerative process had reached the point of femoral subchondral bone exposure.
Squalene monooxygenase – a target for hypercholesterolemic therapy
Authors: Belter Agnieszka , Skupinska Miroslawa , Giel-Pietraszuk Malgorzata , Grabarkiewicz Tomasz , Rychlewski Leszek , Barciszewski Jan 
Published: November 2011

AbstractSqualene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in eukaryotes. Sterols are essential compounds of these organisms and squalene epoxidation is an important regulatory point in their synthesis. Squalene monooxygenase downregulation in vertebrates and fungi decreases synthesis of cholesterol and ergosterol, respectively, which makes squalene monooxygenase a potent and attractive target of hypercholesterolemia and antifungal therapies. Currently some fungal squalene monooxygenase inhibitors (terbinafine, naftifine, butenafine) are in clinical use, whereas mammalian enzymes’ inhibitors are still under investigation. Research on new squalene monooxygenase inhibitors is important due to the prevalence of hypercholesterolemia and the lack of both sufficient and safe remedies. In this paper we (i) review data on activity and the structure of squalene monooxygenase, (ii) present its inhibitors, (iii) compare current strategies of lowering cholesterol level in blood with some of the most promising strategies, (iv) underline advantages of squalene monooxygenase as a target for hypercholesterolemia therapy, and (v) discuss safety concerns about hypercholesterolemia therapy based on inhibition of cellular cholesterol biosynthesis and potential usage of squalene monooxygenase inhibitors in clinical practice. After many years of use of statins there is some clinical evidence for their adverse effects and only partial effectiveness. Currently they are drugs of choice but are used with many restrictions, especially in case of children, elderly patients and women of childbearing potential. Certainly, for the next few years, statins will continue to be a suitable tool for cost-effective cardiovascular prevention; however research on new hypolipidemic drugs is highly desirable. We suggest that squalene monooxygenase inhibitors could become the hypocholesterolemic agents of the future.