bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic kidney disease and bisphosphonate treatment: are prescribing guidelines unnecessarily restrictive?
Authors: Courtney A E , Maxwell A P 
Published: June 2009

AbstractThe prevalence of both osteoporosis and chronic kidney disease (CKD) increases with advancing age. Bisphosphonates are effective in the prevention and treatment of osteoporosis but current recommendations limit their use in patients with renal impairment because of concern regarding the safety profile of these agents in the setting of reduced renal function. The appropriateness of bisphosphonate treatment for patients with CKD is also in question since CKD is independently associated with a variety of skeletal abnormalities, collectively termed renal osteodystrophy, including pre-existing low bone turnover. The evidence to support the current prescribing restrictions is not robust and there are some data to suggest both that bisphosphonate treatment reduces fracture risk without an increase in adverse events in patients with CKD, and that in clinical practice there is underutilisation of this treatment in early CKD. Appropriate prospective trial data with clinically important end points in CKD patients is awaited.
Mountain mortality: a review of deaths that occur during recreational activities in the mountains
Authors: Windsor J S , Firth P G , Grocott M P , Rodway G W , Montgomery H E 
Published: June 2009

AbstractThe growing popularity of activities such as hiking, climbing, skiing and snowboarding has ensured that the number of visitors to mountain environments continues to increase. Since such areas place enormous physical demands on individuals, it is inevitable that deaths will occur. Differences in the activities, conditions and methods of calculation make meaningful mortality rates difficult to obtain. However, it is clear that the mortality rate for some mountain activities is comparable to hang gliding, parachuting, boxing and other pastimes that are traditionally viewed as dangerous. Deaths in the mountains are most commonly due to trauma, high altitude illness, cold injury, avalanche burial and sudden cardiac death. This review describes the mortality rates of those who undertake recreational activities in the mountains and examines the aetiology that lies behind them.
COMPARING ENTROPIC AND MULTIPLE RELAXATION TIMES LATTICE BOLTZMANN METHODS FOR BLOOD FLOW SIMULATIONS
Authors: GEERDINK JOOST B. W. , HOEKSTRA ALFONS G. 
Published: June 2009

We compare the Lattice BGK, the Multiple Relaxation Times and the Entropic Lattice Boltzmann Methods for time harmonic flows. We measure the stability, speed and accuracy of the three models for Reynolds and Womersley numbers that are representative for human arteries.The Lattice BGK shows predictable stability and is the fastest method in terms of lattice node updates per second. The Multiple Relaxation Times LBM shows erratic stability which depends strongly on the relaxation times set chosen and is slightly slower. The Entropic LBM gives the best stability at the price of fewer lattice node updates per second.A parameter constraint optimization technique is used to determine which is the fastest model given a certain preset accuracy. It is found that the Lattice BGK performs best at most arterial flows, except for the high Reynolds number flow in the aorta, where the Entropic LBM is the fastest method due to its better stability. However we also conclude that the Entropic LBM with velocity/pressure inlet/outlet conditions shows much worse performance.
PARALLELIZATION OF REVERSIBLE RIPPLE-CARRY ADDERS
Authors: THOMSEN MICHAEL KIRKEDAL , AXELSEN HOLGER BOCK 
Published: June 2009

The design of fast arithmetic logic circuits is an important research topic for reversible and quantum computing. A special challenge in this setting is the computation of standard arithmetical functions without the generation of garbage. Here, we present a novel parallelization scheme wherein m parallel k-bit reversible ripple-carry adders are combined to form a reversible mk-bit ripple-block carry adder with logic depth [Formula: see text] for a minimal logic depth [Formula: see text], thus improving on the mk-bit ripple-carry adder logic depth [Formula: see text]. The underlying mechanisms of the parallelization scheme are formally proven correct. We also show designs for garbage-less reversible comparison circuits. We compare the circuit costs of the resulting ripple-block carry adder with known optimized reversible ripple-carry adders in measures of circuit delay, width, gate, transistor count, and relative power efficiency, and find that the parallelized adder offers significant speedups at realistic word sizes with modest parallelization overhead.
PRECISE EYE AND MOUTH LOCALIZATION
Authors: CAMPADELLI P. , LANZAROTTI R. , LIPORI G. 
Published: June 2009

The literature on the topic has shown a strong correlation between the degree of precision of face localization and the face recognition performance. Hence, there is a need for precise facial feature detectors, as well as objective measures for their evaluation and comparison. In this paper, we will present significant improvements to a previous method for precise eye center localization, by integrating a module for mouth localization. The technique is based on Support Vector Machines trained on optimally chosen Haar wavelet coefficients. The method has been tested on several public databases; the results are reported and compared according to a standard error measure. The tests show that the algorithm achieves high precision of localization.
EFFECT OF RESTRICTION AND FLOW REYNOLDS NUMBER TO STUDY THE VARIATION OF HEMODYNAMIC PARAMETERS ACROSS COSINE SHAPED STENOTIC MODEL
Authors: BANERJEE MOLOY KUMAR , GANGULY RANJAN , DATTA AMITAVA 
Published: June 2009

Arterial stenosis refers to the swelling of the endothelial wall due to plaque deposition and the associated disease is known as atherosclerosis. A stenosed artery reduces the maximum flow of blood through it by putting more resistance to the flow. The pressure of blood in a coronary artery is considered to be one of the important contributors for the formation and progression of atherosclerosis. Therefore, in this paper, the impact of flow Reynolds number (Re) and degree of stenosis (S) on wall pressure near the stenosis in a part of coronary artery is studied considering laminar flow and modeling blood as both Newtonian and non-Newtonian fluid. The two-dimensional steady differential equations for conservation of mass and momentum is solved by finite difference method through stenosed arteries having mild (S = 25%) to severe (S = 65%) occlusions and under different regimes of flow Reynolds numbers ranging from 50 to 400. From the study, it is revealed that for all the cases a sharp variation in dimensionless wall pressure is observed near the zone of restriction. The peak centerline velocity and the peak value of wall shear stress (WSS), in the stenosed region is more sensitive to a change in the degree of occlusion rather than change in the flow Re. From the study it is also revealed that at high Re regime the irreversible pressure loss coefficient (CI) becomes insensitive to Re values and can be approximated to be a function of S only.
Successes and Challenges in Translational Research: The Development of Targeted Therapy for Gastrointestinal Stromal Tumours
Authors: Renouf Daniel J. , Wilson Lora , Blanke Charles D. 
Published: June 2009

Abstract
Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms that most commonly affect the stomach or small intestine, but that can occur anywhere within the gastrointestinal tract. The annual incidence of GISTs is estimated to be 10 to 20 cases per million. Traditionally, the only effective treatment was surgical resection, and recurrences were common even with complete removal of tumor. Systemic therapy with standard cytotoxic chemotherapeutic agents was completely ineffective. A series of exciting laboratory developments led to the discovery that the small molecule tyrosine kinase inhibitor STI571 (imatinib mesylate) has significant clinical activity in GISTs, representing one of the first therapeutic uses of a targeted agent directed against a solid tumor. In this article we will describe the key steps that led to the initial clinical trials of imatinib in GISTs, and we will also discuss the process of incorporating this novel therapy into mainstream oncologic practice.
Global Gene Expression Analysis of Reactive Stroma in Prostate Cancer
Authors: Dakhova Olga , Ozen Mustafa , Creighton Chad J. , Li Rile , Ayala Gustavo , Rowley David , Ittmann Michael 
Published: June 2009

Abstract
Purpose: Marked reactive stroma formation, designated as grade 3 reactive stroma, is associated with poor outcome in clinically localized prostate cancer. To understand the biological processes and signaling mechanisms underlying the formation of such reactive stroma, we carried out microarray gene expression analysis of laser-captured reactive stroma and matched normal stroma.
Experimental Design: Seventeen cases of reactive stroma grade 3 cancer were used to laser-capture tumor and normal stroma. Expression analysis was carried out using Agilent 44K arrays. Up-regulation of selected genes was confirmed by quantitative reverse transcription-PCR. Expression data was analyzed to identify significantly up- and down-regulated genes, and gene ontology analysis was used to define pathways altered in reactive stroma.
Results: A total of 544 unique genes were significantly higher in the reactive stroma and 606 unique genes were lower. Gene ontology analysis revealed significant alterations in a number of novel processes in prostate cancer reactive stroma, including neurogenesis, axonogenesis, and the DNA damage/repair pathways, as well as evidence of increases in stem cells in prostate cancer reactive stroma.
Conclusions: Formation of reactive stroma in prostate cancer is a dynamic process characterized by significant alterations in growth factor and signal transduction pathways and formation of new structures, including nerves and axons.
A Phase I Study of Eribulin Mesylate (E7389), a Mechanistically Novel Inhibitor of Microtubule Dynamics, in Patients with Advanced Solid Malignancies
Authors: Goel Sanjay , Mita Alain C. , Mita Monica , Rowinsky Eric K. , Chu Quincy S. , Wong Nancy , Desjardins Christopher , Fang Fang , Jansen Mendel , Shuster Dale E. , Mani Sridhar , Takimoto Chris H. 
Published: June 2009

Abstract
Purpose: Eribulin mesylate (E7389), a non-taxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analogue of halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This phase I study determined the maximum tolerated dose (MTD) and pharmacokinetics of eribulin administered on a 3 of 4 week schedule in patients with advanced solid malignancies.
Experimental Design: Patients received eribulin mesylate (1-hour i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. Dosing began at 0.25 mg/m2 with escalation guided by dose-limiting toxicities (DLT). MTD, DLTs, safety, pharmacokinetics, and antitumor activity were characterized.
Results: Thirty-two patients received eribulin mesylate (0.25, 0.5, 0.7, 1.0, or 1.4 mg/m2). Neutropenia was the principal DLT: At 1.4 mg/m2, two patients experienced grade 4 neutropenia, one of whom also developed grade 3 fatigue; three additional patients experienced grade 3 neutropenia and were not treated during cycle 1 on day 15. Therefore, the MTD was 1.0 mg/m2. Fatigue (53% overall, 13% grade 3, no grade 4), nausea (41%, all grade 1/2), and anorexia (38% overall, 3% grade 3, no grade 4) were the most common eribulin-related adverse events. Eight patients reported grade 1/2 neuropathy (no grade 3/4). Eribulin pharmacokinetics were dose-proportional over the dose range studied. One patient (cervical cancer) achieved an unconfirmed partial response lasting 79 days. Ten patients reported stable disease.
Conclusions: Eribulin mesylate, given on days 1, 8, and 15 of a 28-day cycle, exhibits manageable tolerability at 1.0 mg/m2 with further dose escalation limited by neutropenia and fatigue.
High Efficacy of Panobinostat Towards Human Gastrointestinal Stromal Tumors in a Xenograft Mouse Model
Authors: Floris Giuseppe , Debiec-Rychter Maria , Sciot Raf , Stefan Cristiana , Fieuws Steffen , Machiels Kathleen , Atadja Peter , Wozniak Agnieszka , Faa Gavino , Schöffski Patrick 
Published: June 2009

AbstractPurpose: Histone deacetylase inhibitors have emerged as potent anticancer compounds. Using a nude-mouse xenograft model, for the first time we evaluated the response of human gastrointestinal stromal tumors (GIST) carrying different oncogenic KIT mutations to panobinostat (LBH589), administered single or in combination with imatinib.Experimental Design: We grafted the human GIST882 cell line with KIT exon 13 mutation and two biopsies from patients radiologically progressing under imatinib showing KIT exon11 and KIT exon9 mutations, respectively. Our study included 4 groups: A (n = 9; control), B (n = 10; panobinostat 10 mg/kg daily, i.p.), C (n = 9; imatinib 150 mg/kg bidaily, p.o), and D (n = 8; combination panobinostat-imatinib, same dose/schedule as above). Treatment lasted 12 days. Tumor size was measured regularly using standard variables. Histopathological assessment was by H&E, and immunohistochemically with KIT, cleaved caspase-3, Ki-67, and histone acetylation staining.Results: Overall, GIST xenografts responded rapidly to panobinostat as indicated by tumor regression, necrosis, hemorrhages, fibrosis, and/or myxoid degeneration, remarkable apoptosis, and substantial decline of cell proliferation. H3 and H4 acetylation increased significantly from control level in all treated groups. The combination of panobinostat and imatinib further enhanced most of the assessed parameters.Conclusions: We show for the first time potential therapeutic activity of panobinostat in human GISTs, in vivo. Our results warrant further exploration of histone deacetylase inhibitors for the treatment of advanced GISTs. Our study is also the first one on human GIST mouse xenografts established using patient biopsies.
Phase I Trial of Pazopanib in Patients with Advanced Cancer
Authors: Hurwitz Herbert I. , Dowlati Afshin , Saini Shermini , Savage Shawna , Suttle A. Benjamin , Gibson Diana M. , Hodge Jeffrey P. , Merkle Elmar M. , Pandite Lini 
Published: June 2009

Abstract
Purpose: The safety, pharmacokinetics, and clinical activity of pazopanib (GW786034), an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, were evaluated in patients with advanced-stage refractory solid tumors.
Experimental Design: Patients were enrolled into sequential dose-escalating cohorts (50 mg three times weekly to 2,000 mg once daily and 300-400 mg twice daily). Escalation or deescalation was based on toxicities observed in the preceding dose cohort. Pharmacokinetic and biomarker samples were obtained. Clinical response was assessed every 9 weeks.
Results: Sixty-three patients were treated (dose escalation, n = 43; dose expansion, n = 20). Hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mg once daily. A plateau in steady-state exposure was observed at doses of ≥800 mg once daily. The mean elimination half-life at this dose was 31.1 hours. A mean target trough concentration (C24) ≥15 μg/mL (34 μmol/L) was achieved at 800 mg once daily. Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of ≥6 months was observed in 14 patients; clinical benefit was generally observed in patients who received doses of ≥800 mg once daily or 300 mg twice daily.
Conclusion: Pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.
Cytotoxicity Mediated by Histone Deacetylase Inhibitors in Cancer Cells: Mechanisms and Potential Clinical Implications
Authors: Schrump David S. 
Published: June 2009

Abstract
Aberrant expression of epigenetic regulators of gene expression contributes to initiation and progression of cancer. During recent years, considerable research efforts have focused on the role of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in cancer cells, and the identification of pharmacologic agents that modulate gene expression via inhibition of HDACs. The following review highlights recent studies pertaining to HDAC expression in cancer cells, the plieotropic mechanisms by which HDAC inhibitors (HDACi) mediate antitumor activity, and the potential clinical implications of HDAC inhibition as a strategy for cancer therapy.
Superior Antitumor Activity of SAR3419 to Rituximab in Xenograft Models for Non-Hodgkin's Lymphoma
Authors: Al-Katib Ayad M. , Aboukameel Amro , Mohammad Ramzi , Bissery Marie-Christine , Zuany-Amorim Claudia 
Published: June 2009

AbstractPurpose: To investigate the activity of SAR3419, a novel humanized anti-CD19 antibody (huB4), conjugated to a cytotoxic maytansine derivative N2'-deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl) maytansine, in preclinical xenograft models for non–Hodgkin's lymphoma.Experimental Design: Antitumor activity of SAR3419 was assessed as a single agent and in comparison with conventional therapies using a subcutaneous model for diffuse large B-cell lymphoma (WSU-DLCL2) and a systemic model for follicular small cleaved cell lymphoma (WSU-FSCCL) in mice with severe combined immune deficiency.Results: Our results showed that in these chemotherapy-resistant models, SAR3419 was more effective than CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone) regimen or rituximab. Only treatment with SAR3419 led to survival of the whole group of animals to the end of the experiment (150-155 days) in both models. Higher doses of SAR3419 (15 and 30 mg/kg) were more effective than lower dose of 7.5 mg/kg. The immunoconjugation was necessary because neither huB4 nor DM4 alone had significant activity. Treatment with rituximab resulted in antitumor activity in both models comparable with the low dose of SAR3419. Cyclophosphamide-Adriamycin-vincristine-prednisone alone showed modest activity in both models. Necropsy and tissue staining in the WSU-FSCCL systemic model revealed that all deaths featured leptomeningeal lymphoma in the control and treated groups. Interestingly, some of the animals that survived to the end of the experiment and seemed healthy at time of euthanasia did show microscopic evidence of lymphoma.Conclusions: Overall, SAR3419 is a very active immunotoxin in preclinical models for human B-cell lymphoma and holds promise as a novel and well-tolerated therapy in B-cell non–Hodgkin's lymphoma.
Fibroblast Growth Factor Receptor 2–Positive Fibroblasts Provide a Suitable Microenvironment for Tumor Development and Progression in Esophageal Carcinoma
Authors: Zhang Chunyu , Fu Li , Fu Jianhua , Hu Liang , Yang Hong , Rong Tie-Hua , Li Yan , Liu Haibo , Fu Song-Bin , Zeng Yi-Xin , Guan Xin-Yuan 
Published: June 2009

Abstract
Purpose: Tumor fibroblasts (TF) have been suggested to play an essential role in the complex process of tumor-stroma interactions and tumorigenesis. The aim of the present study was to investigate the specific role of TF in the esophageal cancer microenvironment.
Experimental Design: An Affymetrix expression microarray was used to compare gene expression profiles between six pairs of TFs and normal fibroblasts from esophageal squamous cell carcinoma (ESCC). Differentially expressed genes were identified, and a subset was evaluated by quantitative real-time PCR and immunohistochemistry.
Results: About 43% (126 of 292) of known deregulated genes in TFs were associated with cell proliferation, extracellular matrix remodeling, and immune response. Up-regulation of fibroblast growth factor receptor 2 (FGFR2), which showed the most significant change, was detected in all six tested TFs compared with their paired normal fibroblasts. A further study found that FGFR2-positive fibroblasts were only observed inside the tumor tissues and not in tumor-surrounding stromal tissues, suggesting that FGFR2 could be used as a TF-specific marker in ESCC. Moreover, the conditioned medium from TFs was found to be able to promote ESCC tumor cell growth, migration, and invasion in vitro.
Conclusions: Our study provides new candidate genes for the esophageal cancer microenvironment. Based on our results, we hypothesize that FGFR2(+)-TFs might provide cancer cells with a suitable microenvironment via secretion of proteins that could promote cancer development and progression through stimulation of cancer cell proliferation, induction of angiogenesis, inhibition of cell adhesion, enhancement of cell mobility, and promotion of the epithelial-mesenchymal transition.
Targeting GIPC/Synectin in Pancreatic Cancer Inhibits Tumor Growth
Authors: Muders Michael H. , Vohra Pawan K. , Dutta Shamit K. , Wang Enfeng , Ikeda Yasuhiro , Wang Ling , Udugamasooriya D. Gomika , Memic Adnan , Rupashinghe Chamila N. , Baretton Gustavo B. , Aust Daniela E. , Langer Silke , Datta Kaustubh , Simons Michael , Spaller Mark R. , Mukhopadhyay Debabrata 
Published: June 2009

Abstract
Purpose: Various studies have shown the importance of the GAIP interacting protein, COOH-terminus (GIPC, also known as Synectin) as a central adaptor molecule in different signaling pathways and as an important mediator of receptor stability. GIPC/Synectin is associated with different growth-promoting receptors such as insulin-like growth factor receptor I (IGF-IR) and integrins. These interactions were mediated through its PDZ domain. GIPC/Synectin has been shown to be overexpressed in pancreatic and breast cancer. The goal of this study was to show the importance of GIPC/Synectin in pancreatic cancer growth and to evaluate a possible therapeutic strategy by using a GIPC-PDZ domain inhibitor. Furthermore, the effect of targeting GIPC on the IGF-I receptor as one of its associated receptors was tested.
Experimental Design: The in vivo effects of GIPC/Synectin knockdown were studied after lentiviral transduction of luciferase-expressing pancreatic cancer cells with short hairpin RNA against GIPC/Synectin. Additionally, a GIPC-PDZ–targeting peptide was designed. This peptide was tested for its influence on pancreatic cancer growth in vitro and in vivo.
Results: Knockdown of GIPC/Synectin led to a significant inhibition of pancreatic adenocarcinoma growth in an orthotopic mouse model. Additionally, a cell-permeable GIPC-PDZ inhibitor was able to block tumor growth significantly without showing toxicity in a mouse model. Targeting GIPC was accompanied by a significant reduction in IGF-IR expression in pancreatic cancer cells.
Conclusions: Our findings show that targeting GIPC/Synectin and its PDZ domain inhibits pancreatic carcinoma growth and is a potential strategy for therapeutic intervention of pancreatic cancer.