bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vertical Targeting of the Phosphatidylinositol-3 Kinase Pathway as a Strategy for Treating Melanoma
Authors: Aziz Saadia A. , Jilaveanu Lucia B. , Zito Christopher , Camp Robert L. , Rimm David L. , Conrad Patricia , Kluger Harriet M. 
Published: December 2010

Abstract
Purpose: Melanoma is relatively resistant to chemotherapy; improved targeting of molecules critical for cell proliferation and survival are needed. Phosphatidylinositol-3 kinase (PI3K) is an important target in melanoma; however, activity of PI3K inhibitors (PI3KI) is limited. Our purpose was to assess mTOR as a cotarget for PI3K.
Methods: Using a method of quantitative immunofluorescence to measure mTOR expression in a large melanoma cohort, we studied associations with PI3K subunits, p85 and p110α. We assessed addition of the mTOR inhibitor rapamycin to 2 PI3KIs, NVP-BKM120 and LY294002. We studied in vitro activity of a novel dual PI3K/mTOR inhibitor NVP-BEZ235 and activity of the combination of NVP-BEZ235 and the MAP/ERK kinase (MEK) inhibitor AZD6244.
Results: Strong coexpression of mTOR and p110α was observed (ρ = 0.658; P &lt; 0.0001). Less coexpression was seen with p85 (ρ = 0.239; P &lt; 0.0001). Strong synergism was shown between rapamycin and both PI3KIs. Activity of both PI3KIs was similarly enhanced with all rapamycin concentrations used. The dual PI3K/mTOR inhibitor effectively inhibited viability in 23 melanoma cell lines (IC50 values in the nanomolar range), regardless of B-Raf mutation status, with resultant reduction in clonogenicity and downregulation of pAkt and pP70S6K. Synergism was seen when combining NVP-BEZ235 and AZD6244, with resultant increases in poly(ADP-ribose) polymerase and caspase-2 cleavage.
Conclusions: mTOR and p110α are coexpressed in melanoma. Rapamycin concentrations as low as 1 nmol/L enhance activity of PI3KIs. The dual PI3K/mTOR inhibitor NVP-BEZ235 is highly active in melanoma cells in vitro, suggesting that concurrent PI3K and mTOR targeting in melanoma warrants further investigation, both alone and in combination with MEK inhibitors.
Intrinsic Breast Tumor Subtypes, Race, and Long-Term Survival in the Carolina Breast Cancer Study
Authors: O'Brien Katie M. , Cole Stephen R. , Tse Chiu-Kit , Perou Charles M. , Carey Lisa A. , Foulkes William D. , Dressler Lynn G. , Geradts Joseph , Millikan Robert C. 
Published: December 2010

Abstract
Purpose: Previous research identified differences in breast cancer–specific mortality across 4 intrinsic tumor subtypes: luminal A, luminal B, basal-like, and human epidermal growth factor receptor 2 positive/estrogen receptor negative (HER2+/ER−).
Experimental Design: We used immunohistochemical markers to subtype 1,149 invasive breast cancer patients (518 African American, 631 white) in the Carolina Breast Cancer Study, a population-based study of women diagnosed with breast cancer. Vital status was determined through 2006 using the National Death Index, with median follow-up of 9 years.
Results: Cancer subtypes luminal A, luminal B, basal-like, and HER2+/ER− were distributed as 64%, 11%, 11%, and 5% for whites, and 48%, 8%, 22%, and 7% for African Americans, respectively. Breast cancer mortality was higher for participants with HER2+/ER− and basal-like breast cancer compared with luminal A and B. African Americans had higher breast cancer–specific mortality than whites, but the effect of race was statistically significant only among women with luminal A breast cancer. However, when compared with the luminal A subtype within racial categories, mortality for participants with basal-like breast cancer was higher among whites (HR = 2.0, 95% CI: 1.2–3.4) than African Americans (HR = 1.5, 95% CI: 1.0–2.4), with the strongest effect seen in postmenopausal white women (HR = 3.9, 95% CI: 1.5–10.0).
Conclusions: Our results confirm the association of basal-like breast cancer with poor prognosis and suggest that basal-like breast cancer is not an inherently more aggressive disease in African American women compared with whites. Additional analyses are needed in populations with known treatment profiles to understand the role of tumor subtypes and race in breast cancer mortality, and in particular our finding that among women with luminal A breast cancer, African Americans have higher mortality than whites. Clin Cancer Res; 16(24); 6100–10. ©2010 AACR.
Evaluating Patient-Centered Outcomes in the Randomized Controlled Trial and Beyond: Informing the Future with Lessons from the Past
Authors: Booth Christopher M. 
Published: December 2010

Abstract
In the era of molecular oncology, patients still define a useful therapy as one that allows them to live longer and helps them to live better. Although patient outcomes have clearly improved as a result of randomized controlled trials (RCT), it is critical that contemporary trials retain the perspective of these fundamental patient-centered outcomes. Trends in study design, results, and interpretation of oncology RCTs from the past provide a useful framework in which to consider how the research community may approach trial design in the future. Although the RCT remains the standard for establishing efficacy, this article also considers how population-based outcome studies can provide insight into effectiveness of new therapies and explores how the results of RCTs translate into benefit in the general population. Clin Cancer Res; 16(24); 5963–71. ©2010 AACR.
Aerosolized Bexarotene Inhibits Lung Tumorigenesis without Increasing Plasma Triglyceride and Cholesterol Levels in Mice
Authors: Zhang Qi , Pan Jing , Zhang Jingjie , Liu Pengyuan , Chen Ruth , Chen Da-ren , Lubet Ronald , Wang Yian , You Ming 
Published: December 2010

Abstract
Prior studies have shown the retinoid X receptor (RXR) agonist bexarotene has preventive efficacy in rodent models of mammary and lung tumorigenesis albeit causing hypertriglyceridemia and hypercholesterolemia. We reasoned that bexarotene delivered by inhalation may provide sufficient dose directly to the respiratory tract to achieve efficacy while avoiding these side effects. In this study, the chemopreventive activity of aerosolized bexarotene was investigated in the benzo(a)pyrene [B(a)P]-induced mouse lung tumor model as assessed by tumor multiplicity and tumor load. Aerosolized bexarotene significantly decreased tumor multiplicity and tumor load by 43% and 74%, respectively. Our data showed that bexarotene can both inhibit proliferation and promote apoptosis in vivo. Our data also show that aerosolized bexarotene did not increase plasma total cholesterol and triglyceride level compared with diet group. These results indicate that aerosolization may be a safe and effective route of administering bexarotene for chemoprevention of lung cancer. Cancer Prev Res; 4(2); 270–6. ©2010 AACR.
Cyclooxygenase-2 Mediates Hyperbaric Oxygen Preconditioning in the Rat Model of Transient Global Cerebral Ischemia
Authors: Cheng Oumei , Ostrowski Robert P. , Wu Bihua , Liu Wenwu , Chen Chunhua , Zhang John H. 
Published: December 2010

Background and Purpose—
Hyperbaric oxygen (HBO) preconditioning (PC) allows brain protection against transient global ischemia. In the present study, we hypothesize that the mechanism of HBO-PC involves the induction of cyclooxygenase-2 (COX-2) in cerebral tissues before ischemia, which leads to a suppression of COX-2 and its downstream targets after global ischemic insult.

Methods—
One hundred twenty-nine male Sprague Dawley rats (body weight 280–300 grams) were allocated to the naive control group and the sham operation group, and 3 groups of animals were subjected to 15-minute 4-vessel occlusion: untreated, preconditioned with HBO 2.5 atmospheres absolutes for 1 hour daily for 5 days, preconditioned as mentioned and administered with COX-2 inhibitor NS-398 (1 mg/kg body weight intraperitoneal) before each preconditioning session, and normal rats preconditioned with HBO without ischemia. The mortality, the incidence of seizures, and T-maze scores were recorded. The quantitative cell count in Nissl stain and TUNEL was conducted on day 7 after ischemia. The brain expression of COX-2 was analyzed with Western blotting and immunofluorescence staining.

Results—

HBO-PC increased the number of surviving neurons in the
Cornu Ammonis
area 1, which was associated with the reduced COX-2 expression in the hippocampus and in the cerebral cortex at 1 and 3 days after ischemia. HBO-PC improved functional performance and tended to decrease mortality and the frequency of seizures. These beneficial effects of HBO-PC were abolished by the COX-2 selective inhibitor NS-398.

Conclusions—
HBO-PC reduced COX-2 expression and provided brain protection after global ischemia. Administration of COX-2 inhibitor with HBO before ischemia abolished preconditioning effect, thereby implicating COX-2 as a mediator of HBO-PC in the ischemic brain.
”Lost in the Revolution“: Bukharan waqf and Testimony Documents from the Early Soviet Period
Authors: Reichmuth Philipp 
Published: December 2010

AbstractAfter the conquest of the Emirate of Bukhara by the Red Army in August and September 1920 and the proclamation of the Bukharan People's Soviet Republic (Buxarskaja Narodnaja Sovetskaja Respublika, BNSR) on 20 September, Islamic institutions in the former emirate were subjected to considerable political, institutional and personal changes that continued throughout the first half of the 1920s, when the BNSR was first declared a Soviet Socialist Republic (BSSR) in September 1924 and then integrated into the newly-formed Uzbek SSR in November of the same year. The institution of pious endowments (waqf) was no exception to these changes. In this article, we shall take a document-centered approach by giving an overview of early Soviet waqf documents from Bukhara kept in the Central State Archive of Uzbekistan in Tashkent (CGA RUz). Research on waqf in Soviet Turkestan has focused mainly on the ASSR and not on the former protectorates with their longer heritage of Islamic statehood, and it does not look on waqf documents themselves. Since these documents represent one end of the trajectory of the development of Islamic chancery practice before the abolition of the institutions that produced such documents, their study can add to our understanding of the diplomatics of Persian-language private documents in general. This article will give an overview of the collection of post-1920 waqf documents in the CGA. It then illustrates the basic structure and content of documents for newly-established endowments, finally comparing them with documents of testimony for existing awqāf. For this analysis a specific structural model is developed and applied to these documents.
Holiness and Order: British Methodism's Search for the Holy Catholic Church
Authors: Chapman David 
Published: December 2010

AbstractThis article investigates British Methodism's doctrine of the Church in relation to its own ecclesial self-understanding. Methodists approach the doctrine of the Church by reflecting on their 'experience' and 'practice', rather than systematically. The article sketches the cultural and ecclesial context of Methodist ecclesiology before investigating the key sources of British Methodist doctrinal teaching on the Church: the theological legacy of John Wesley; the influence of the non-Wesleyan Methodist traditions as represented by Primitive Methodism; twentieth-century ecumenical developments; and British Methodist Faith and Order statements on the subject. The phenomenon of 'emerging expressions of Church' makes the question of the nature and location of the Church pertinent at the present time for all Christian traditions.
Taking Hobbes at His Word: Comments on Morality in the Philosophy of Thomas Hobbes by S.A. Lloyd
Authors: Rhodes Rosamond 
Published: December 2010

AbstractThis paper focuses on S.A. Loyd's positive account of Hobbes's moral theory as presented in chapters 5 and 6 of her new book. My discussion challenges Lloyd's reciprocity interpretation of Hobbes's moral theory. In the paper I also take issue with Lloyd's account of the derivation of his moral theory and her account of moral obligation. I offer my own definitional reading of the derivation of the Laws of Nature and my own analysis of how Hobbes explains obligation in terms of assent.
Effects of Charge Distribution in Thunderstorms on Lightning Propagation Paths in Darwin, Australia
Authors: Akita Manabu , Yoshida Satoru , Nakamura Yoshitaka , Morimoto Takeshi , Ushio Tomoo , Kawasaki Zen , Wang Daohong 
Published: December 2010

Abstract
The charge distributions in a thundercloud play an important role in the initiation and propagation of lightning discharges. To further understand the effects of charge distributions on lightning discharge, the authors conducted a very high-frequency (VHF) lightning observation campaign during the 2006/07 monsoon in Darwin, Australia, using a VHF broadband digital interferometer (DITF). A C-band polarimetric weather radar to estimate the precipitation profiles such as hydrometeor classification was operated by the Bureau of Meteorology (BOM) Research Centre. Cloud-to-ground (CG) and intracloud (IC) flashes were initiated from the outer and the inner parts of the upper side of the graupel regions, respectively. In the cases of CG flashes, the negative leaders travel first about 10 km horizontally through positive charge regions and then begin to bend toward the ground when they reach the edge of the positive charge regions where there is no graupel region underneath. In contrast, in the cases of the IC flashes the negatively charged graupel regions block the downward developments of negative leaders. It is noted that positive charge regions could facilitate the extension of the horizontal negative leader. These results may suggest that lightning flash types are closely dependent on their initiation locations and the surrounding charge distributions. The experimental results are consistent with other previous observation results and charge model simulations.
Anterolateral Transtibial Posterior Cruciate Ligament Reconstruction Combined With Anatomical Reconstruction of Posterolateral Corner Insufficiency
Authors: Kim Sung-Jae , Jung Min , Moon Hong-Kyo , Kim Sul-Gee , Chun Yong-Min 
Published: December 2010

Background: There is a paucity of clinical studies comparing single- and double-bundle posterior cruciate ligament (PCL) reconstruction combined with a posterolateral corner reconstruction. Purpose: To compare the clinical outcomes of single- and double-bundle transtibial PCL reconstruction combined with reconstruction of the lateral collateral ligament and popliteus tendon for posterolateral corner insufficiency. Study Design: Cohort study; Level of evidence 3. Methods: The study population consisted of 42 patients for whom a minimum of 2 years of follow-up data were available. The authors compared the clinical outcomes of 2 surgical techniques: a single-bundle technique (23 patients) and a double-bundle technique (19 patients), each combined with reconstruction of the lateral collateral ligament and popliteus tendon for posterolateral corner insufficiency. Results: There was no significant difference between the single- and double-bundle groups in mean side-to-side difference of posterior translation as measured with Telos stress radiography (4.2 ± 1.7 vs 3.9 ± 1.6 mm; P = .628). Rates of residual increased laxity greater than 5 mm were 22% in the single-bundle group and 21% in the double-bundle group. Regarding posterolateral rotatory instability, there were no differences between the 2 groups in mean side-to-side difference in the dial test (5.3° ± 2.7° vs 5.1° ± 2.4° at 30° of flexion [ P = .800]; 6.7° ± 2.7° vs 6.7° ± 2.4° at 90° of flexion [ P = .917]) or in varus stress radiography (1.2 ± 1.2 vs 1.3 ± 1.4 mm; P = .722). The Lysholm knee scores were 85.7 ± 7.6 in the single-bundle group and 87.7 ± 7.3 in the double-bundle group, and there was no significant difference between them ( P = .392). There was also no difference between the groups in International Knee Documentation Committee knee score ( P = .969); from this, the rates of abnormal and severely abnormal were 30% in the single-bundle group and 26% in the double-bundle group. Conclusion: In this series, double-bundle PCL reconstruction combined with posterolateral corner reconstruction did not appear to have advantages over single-bundle PCL reconstruction combined with posterolateral corner reconstruction with respect to the clinical outcomes or posterior knee stability.
Long-Term Results of Ulnar Collateral Ligament Reconstruction in Throwing Athletes Based on a Hybrid Technique
Authors: Hechtman Keith S. , Zvijac John E. , Wells Matt E. , Botto-van Bemden Angie 
Published: December 2010

Background: Tearing or attenuation of the ulnar collateral ligament (UCL) of the elbow is a common injury in the throwing athlete. Several techniques for reconstruction of the attenuated or torn UCL have been developed. Hypothesis: Ulnar collateral ligament reconstruction based on a hybrid technique, with an ulnar osseous tunnel and suture anchor fixation on the humerus, allows throwing athletes to return to prior activity level and has a low complication rate. Study Design: Case series; Level of evidence, 4. Methods: A retrospective review was performed of the UCL reconstructions performed in 34 throwing athletes, as based on a hybrid technique, over a 6-year period. All elbows were reconstructed with a tendon graft fixed through an osseous tunnel placed at the sublime tubercle and with 2 suture anchors placed into a bony trough at the humeral origin of the native ligament. Results: Average postoperative follow-up was 6.9 years (range, 4.2 to 8.7 years). The average age was 20.2 years, with symptoms present for an average of 22.4 weeks before clinic presentation. Each athlete had pain with valgus stress or milking maneuver in addition to a documented tear of the UCL on magnetic resonance imaging. All experienced pain on the medial aspect of the elbow while throwing. Only 1 patient had new onset of temporary ulnar nerve paresthesia, for a complication rate of 2%. Of 34 athletes, 29 (85%) had an excellent result, defined as the ability to return to play at or above preinjury level. Of the 5 patients who did not return to preinjury level, only 2 were unable to do so secondary to pain. Conclusion: Ulnar collateral ligament reconstruction based on a hybrid fixation technique results in a low complication rate and allows full recovery to preinjury level of performance in the majority (85%) of patients.
Relationship between brain MRI lesion load and short-term disease evolution in non-disabling MS: a large-scale, multicentre study
Authors: Rovaris Marco , Rocca Maria A , Barkhof Frederik , Calabrese Massimiliano , De Stefano Nicola , Khalil Michael , Fazekas Franz , Fisniku Leonora , Gallo Paolo , Miller David H , Montalban Xavier , Polman Chris , Rovira Alex , Sombekke Madeleine H , Sormani Maria Pia , Stromillo Maria Laura , Filippi Massimo 
Published: December 2010

Background and Objectives: We evaluated clinical and conventional MRI features of a large population of patients with non-disabling MS to identify potential markers of a benign disease course. Methods: In seven MAGNIMS centres we retrospectively identified 182 patients with benign (B) MS (EDSS score ≤3.0, disease duration ≥15 years) and 187 patients with non-disabling relapsing–remitting MS (NDRRMS) (Expanded Disability Status Scale score ≤3.0, disease duration between 5 and 14 years), in whom clinical data were collected within two weeks from a brain T2-weighted scan. Brain T2 lesion volume (LV) was measured in all patients. In 146 BMS and 146 NDRRMS patients, clinical data were also available after a median follow up of 29 months (range: 7–104 months). Results: Mean LV was higher in BMS than in NDRRMS patients ( p < 0.001), but the mean ratio between LV and disease duration was higher in NDRRMS than in BMS patients (1.1 vs. 0.6 ml/year, p < 0.001). In BMS patients, brain LV was correlated with EDSS score increase at follow up ( r = 0.18, p = 0.03). Conclusions: An overall low rate of brain LV increase during a long-lasting disease course might be a feature of BMS. In BMS patients, a high brain LV might be associated with worsening of locomotor disability at short-term follow up.
Oligoclonal bands predict multiple sclerosis after optic neuritis: a literature survey
Authors: Skov AG , Skov T , Frederiksen JL 
Published: December 2010

Background: Multiple sclerosis (MS) is an autoimmune disease resulting in inflammation and demyelination of neurones in the central nervous system (CNS). The first sign of MS is often monosymptomatic optic neuritis (MON). Cerebrospinal fluid from a patient with MS analysed by electrophoresis often shows a split to form so called oligoclonal bands (OCBs). OCBs consist of proteins from activated lymphocytes and plasma cell clones. Objectives: The aim of this study was to review the published literature on OCBs in MON patients and perform a meta-analysis of the studies in order to assess the utility of OCB determination in patients with MON in the prediction of their risk of MS. Methods: Review and meta-analysis of the results of 10 published studies. Results: OCBs as a predictive test had a sensitivity of 73–100% (mean 88.5%), a specificity of 41–90% (mean 57%) and OR-values between 2.75 and 171 (mean 34.2). The areal under the summary receiver operator characteristic (ROC) curve was 0.89 (unweighted) and 0.82 (weighted). The studies showed large heterogeneity in the diagnostic accuracy. Conclusion: This literature-based meta-analysis provides evidence that OCBs may have a high predictive value for the development of MS in patients with MON. Standardization of laboratory methods and diagnostic criteria would help bring out the full clinical potential of the test. To elucidate the predictive value of OCBs versus MRI, we recommend that a similar meta-analysis of studies of MRI in MON be performed.