bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-related gastrointestinal adverse events
Authors: Shahabi Vafa , Berman David , Chasalow Scott D , Wang Lisu , Tsuchihashi Zenta , Hu Beihong , Panting Lisa , Jure-Kunkel Maria , Ji Rui-Ru 
Published: March 2013

Abstract

Background
Treatment with ipilimumab, a fully human anti-CTLA-4 antibody approved for the treatment of advanced melanoma, is associated with some immune-related adverse events (irAEs) such as colitis (gastrointestinal irAE, or GI irAE) and skin rash, which are managed by treatment guidelines. Nevertheless, predictive biomarkers that can help identify patients more likely to develop these irAEs could enhance the management of these toxicities.

Methods
To identify candidate predictive biomarkers associated with GI irAEs, gene expression profiling was performed on whole blood samples from 162 advanced melanoma patients at baseline, 3 and 11 weeks after the start of ipilimumab treatment in two phase II clinical trials (CA184004 and CA184007). Overall, 49 patients developed Grade 2 or higher (grade 2+) GI irAEs during the course of treatment. A repeated measures analysis of variance (ANOVA) was used to evaluate the differences in mean expression levels between the GI irAE and No-GI irAE groups of patients at the three time points.

Results
In baseline samples, 27 probe sets showed differential mean expression (≥ 1.5 fold, P ≤ 0.05) between the GI irAE and No-GI irAE groups. Most of these probe sets belonged to three functional categories: immune system, cell cycle, and intracellular trafficking. Changes in gene expression over time were also characterized. In the GI irAE group, 58 and 247 probe sets had a ≥ 1.5 fold change in expression from baseline to 3 and 11 weeks after first ipilimumab dose, respectively. In particular, on-treatment expression increases of CD177 and CEACAM1, two neutrophil-activation markers, were closely associated with GI irAEs, suggesting a possible role of neutrophils in ipilimumab-associated GI irAEs. In addition, the expression of several immunoglobulin genes increased over time, with greater increases in patients with grade 2+ GI irAEs.

Conclusions
Gene expression profiling of peripheral blood, sampled before or early in the course of treatment with ipilimumab, resulted in the identification of a set of potential biomarkers that were associated with occurrence of GI irAEs. However, because of the low sensitivity of these biomarkers, they cannot be used alone to predict which patients will develop GI irAEs. Further investigation of these biomarkers in a larger patient cohort is warranted.
Development of a robust flow cytometry-based pharmacodynamic assay to detect phospho-protein signals for phosphatidylinositol 3-kinase inhibitors in multiple myeloma
Authors: Li Congfen , Takahashi Chikara , Zhang Liangxuan , Huseni Mahrukh , Stankovich Basha , Mashhedi Haider , Lee Joanna , French Dorothy , Anderson Jeff Eastham , Kim Doris , Howell Kathy , Brauer Matthew J , Kowanetz Marcin , Yan Yibing , Humke Eric , Ebens Allen , Hampton Garret , Lackner Mark R , Hegde Priti , Jia Shidong 
Published: March 2013

Abstract

Background
The phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in multiple myeloma (MM), a blood cancer associated with uncontrolled proliferation of bone marrow plasma cells. This study aimed to develop a robust clinical pharmacodynamic (PD) assay to measure the on-target PD effects of the selective PI3K inhibitor GDC-0941 in MM patients.

Methods
We conducted an in vitro drug wash-out study to evaluate the feasibility of biochemical approaches in measuring the phosphorylation of S6 ribosomal protein (S6), one of the commonly used PD markers for PI3K pathway inhibition. We then developed a 7-color phospho-specific flow cytometry assay, or phospho flow assay, to measure the phosphorylation state of intracellular S6 in bone marrow aspirate (BMA) and peripheral blood (PB). Integrated mean fluorescence intensity (iMFI) was used to calculate fold changes of phosphorylation. Assay sensitivity was evaluated by comparing phospho flow with Meso Scale Discovery (MSD) and immunohistochemistry (IHC) assays. Finally, a sample handling method was developed to maintain the integrity of phospho signal during sample shipping and storage to ensure clinical application.

Results
The phospho flow assay provided single-cell PD monitoring of S6 phosphorylation in tumor and surrogate cells using fixed BMA and PB, assessing pathway modulation in response to GDC-0941 with sensitivity similar to that of MSD assay. The one-shot sample fixation and handling protocol herein demonstrated exceptional preservation of protein phosphorylation. In contrast, the IHC assay was less sensitive in terms of signal quantification while the biochemical approach (MSD) was less suitable to assess PD activities due to the undesirable impact associated with cell isolation on the protein phosphorylation in tumor cells.

Conclusions
We developed a robust PD biomarker assay for the clinical evaluation of PI3K inhibitors in MM, allowing one to decipher the PD response in a relevant cell population. To our knowledge, this is the first report of an easily implemented clinical PD assay that incorporates an unbiased one-shot sample handling protocol, all (staining)-in-one (tube) phospho flow staining protocol, and an integrated modified data analysis for PD monitoring of kinase inhibitors in relevant cell populations in BMA and PB. The methods described here ensure a real-time, reliable and reproducible PD readout, which can provide information for dose selection as well as help to identify optimal combinations of targeted agents in early clinical trials.
Occurrence of congenital disorders in Swiss sheep
Authors: Greber Deborah , Doherr Marcus , Drögemüller Cord , Steiner Adrian 
Published: March 2013

Abstract

Background
The rates of congenital disorders in Swiss sheep were determined by a questionnaire which was sent to 3,183 members of the Swiss Sheep Breeders’ Association.

Findings
A total of 993 questionnaires were returned, giving a response rate of 31.2%. Of these, 862 questionnaires originated from farms keeping one of the predominant Swiss sheep breeds: Swiss White Alpine sheep, Brown-Headed Meat sheep, Swiss Black Brown Mountain sheep and Valais Blacknose sheep. During a 10-year-period, entropion was reported in 33.6% of the farms, brachygnathia inferior in 29.5%, abdominal/umbilical hernia in 15.9%, cryptorchidism in 10.5% and torticollis in 10.5%. The most significant difference between the four breeds (P < 0.001) occurred for entropion in Swiss White Alpine sheep and Brown-Headed Meat sheep, brachygnathia inferior in Swiss Black Brown Mountain sheep, and scrotal/inguinal hernia in Valais Blacknose sheep. The Swiss White Alpine breed showed a significantly higher animal prevalence of entropion (6.2% in 2011 and 5.5% in 2012) than other breeds (P < 0.001).

Conclusions
These findings indicate a breed-specific necessity for action, particularly regarding Swiss animal welfare legislation, especially entropion in Swiss White Alpine sheep is concerned. In general, careful selection of breeding stock is to be recommended.
THRAP3 Interacts with HELZ2 and Plays a Novel Role in Adipocyte Differentiation
Authors: Katano-Toki Akiko , Satoh Tetsurou , Tomaru Takuya , Yoshino Satoshi , Ishizuka Takahiro , Ishii Sumiyasu , Ozawa Atsushi , Shibusawa Nobuyuki , Tsuchiya Takafumi , Saito Tsugumichi , Shimizu Hiroyuki , Hashimoto Koshi , Okada Shuichi , Yamada Masanobu , Mori Masatomo 
Published: March 2013

AbstractUsing yeast two-hybrid screen, we previously isolated HELZ2 (helicase with zinc finger 2, transcriptional coactivator) that functions as a coregulator of peroxisome proliferator-activated receptorγ (PPARγ). To further delineate its molecular function, we here identified thyroid hormone receptor-associated protein3 (THRAP3), a putative component of the Mediator complex, as a protein stably associating with HELZ2 using immunoprecipitation coupled with mass spectrometry analyses. In immunoprecipitation assays, Thrap3 could associate with endogenous Helz2 as well as Pparg in differentiated 3T3-L1 cells. HELZ2 interacts with the serine/arginine-rich domain and Bcl2 associated transcription factor1-homologous region in THRAP3, whereas THRAP3 directly binds 2 helicase motifs in HELZ2. HELZ2 and THRAP3 synergistically augment transcriptional activation mediated by PPARγ, whereas knockdown of endogenous THRAP3 abolished the enhancement by HELZ2 in reporter assays. Thrap3, similar to Helz2, is evenly expressed in the process of adipogenic differentiation in 3T3-L1 cells. Knockdown of Thrap3 in 3T3-L1 preadipocytes using short-interfering RNA did not influence the expression of Krox20, Klf5, Cebpb, or Cebpd during early stages of adipocyte differentiation, but significantly attenuated the expression of Pparg, Cebpa, and Fabp4/aP2 and accumulation of lipid droplets. Pharmacologic activation of Pparg by troglitazone could not fully restore the differentiation of Thrap3-knockdown adipocytes. In chromatin immunoprecipitation assays, endogenous Helz2 and Thrap3 could be co-recruited, in a ligand-dependent manner, to the PPARγ-response elements in Fabp4/aP2 and Adipoq gene enhancers in differentiated 3T3-L1 cells. These findings collectively suggest that Thrap3 could play indispensable roles in terminal differentiation of adipocytes by enhancing PPARγ-mediated gene activation cooperatively with Helz2.
Minireview: Obesity and Breast Cancer: A Tale of Inflammation and Dysregulated Metabolism
Authors: Simpson Evan R. , Brown Kristy A. 
Published: March 2013

AbstractIn addition to the spectrum of conditions known collectively as the Metabolic Syndrome, obesity is now recognized to be associated with increased risk of several cancers including colon, endometrial, and breast cancer. Obesity and carcinogenesis share 2 characteristics in common. On the one hand, they involve inflammatory pathways, and on the other hand, they involve dysregulated metabolism. In this review we focus on postmenopausal breast cancer and discuss the metabolic and cellular mechanisms whereby obesity and breast cancer are related. Because a majority of postmenopausal breast tumors are estrogen responsive, we include a discussion of the action of obesity-related factors on estrogen formation within the breast.
Identification of Hydrogen-Bonded Oligomers in Associating Liquid by 1H NMR: 1-Phenyl-1-cyclohexanol
Authors: Nagatomo Shigenori , Nobuhira Megumi , Yamamura Yasuhisa , Sumita Masato , Saito Kazuya 
Published: March 2013

Abstract
Nonmonotonous temperature dependence, which suggests formation of closed oligomer(s) via hydrogen-bonds, is detected in heat capacity and dielectric constant of the title compound in the liquid state. The 1H NMR signal of hydroxy protons showed a temperature-dependent fine structure. Quantum-chemical calculations on oligomers of several types revealed that the fine structure is plausibly interpreted as a temperature-dependent formation/destruction of oligomers. A coherent analysis of calorimetric, FT-IR, dielectric, and 1H NMR results shows that the neat liquid of the title compound consists mostly of closed (square) tetramers via H-bonds at lower temperatures, and oligomers with open (or straight) H-bonding and non-H-bonding (monomer) at higher temperature.
Syntheses, Crystal Structures, and Photophysical Properties of Platinum(II) Complexes Containing a Disulfanenitrile Ligand
Authors: Honda Hiroya , Fujii Takayoshi , Kuwabara Junpei , Kanbara Takaki 
Published: March 2013

Abstract
New PtII complexes of bidendate Ph2S(=N(Ph2)S≡N)2 (ndsdsd) ligand were prepared, including the homoleptic complex, i.e., [Pt(ndsdsd)2](hfac)2 (1) (hfac: 1,1,1,5,5,5-hexafluoro-2,4-pentanedionato), and the heteroleptic complexes, [Pt(N^N)(ndsdsd)]X2 [N^N = 1,10-phenanthroline (phen) (2), 4,7-diphenylphenanthroline (bathophen) (3); X = PF6 (a) and ClO4 (b)] and [Pt(C^N)(ndsdsd)]X [C^N = 2-phenylpyridine (ppy) (4) and benzo[h]quinoline (bzq) (5); X = PF6 (a) and ClO4 (b)]. The complexes were characterized by IR, NMR spectroscopy, and elemental analysis. The molecular structures of complexes 1, 2a, and 4b have been elucidated by X-ray crystallographic analysis. The photophysical properties of all complexes were examined. Complexes 2 and 3a are very weakly luminescent in solution, whereas they show highly emissive in the solid state (Φem = 0.11–0.27).
Structural Transition of Lipopolysaccharide and Reduction in the Biological Activity by Amphiphilic Lipid with Cationic Amino Acid
Authors: Li Wenjing , Mochizuki Shinichi , Sakurai Kazuo 
Published: March 2013

Abstract
Lipopolysaccharide (LPS), the endotoxin of Gram-negative bacteria, is a strong elicitor in the immune system by interacting with lipopolysaccharide-binding protein and CD14 with high specificity. The removal of LPS contamination in protein drug products expressed by bacteria is essential in pharmaceutical products for human use. Although polymyxin B (PMB)-immobilized columns are mainly used for removal of LPS, there are some problems, such as high production cost, and the toxicity of ligands. We synthesized aromatic lipids bearing lysine or arginine at the headgroup. These lipids form a complex with LPS through electrostatic interaction between cationic amino acids and phosphate groups in the lipid A backbone. The resultant complexes induce the structural transition of LPS from a cylindrical structure to a vesicle. Addition of amino-lipid/LPS complexes to RAW264.7 cells, a macrophage-like cell line, decrease the LPS activity. The efficiencies are higher than commonly used cationic compounds, such as dioleoyltrimethylammoniumpropane (DOTAP) and PMB. These results show that amphiphilic lipids with cationic amino acids can be used for deactivation of LPS.
Decreased Expression of Intercellular Adhesion Molecules in Acantholytic Squamous Cell Carcinoma Compared With Invasive Well-Differentiated Squamous Cell Carcinoma of the Skin
Authors: Griffin John R. , Wriston Cooper C. , Peters Margot S. , Lehman Julia S. 
Published: March 2013

AbstractIntercellular adhesion proteins are poorly characterized in acantholytic squamous cell carcinoma (ASCC), a more aggressive tumor than nonacantholytic invasive well-differentiated squamous cell carcinoma (SCC) of the skin. In this study we compared expression of Dsg3, E-cadherin, and syndecan-1 in ASCC and SCC. Immunohistochemical detection of Dsg3, E-cadherin, and syndecan-1 in 22 ASCCs and 22 SCCs was graded on a semiquantitative scale for intensity of staining (SI) and degree of circumferential staining (CS) about the cell membrane. Results were assessed by means of conditional logistic regression and χ2 analysis. Dsg3 and E-cadherin expression (SI, CS) was significantly decreased (P &lt; .05) in ASCC compared with SCC, whereas staining for syndecan-1 was similar in the 2 tumor types. Differences in expression of adhesion markers between ASCC and SCC may contribute to the development of acantholysis in ASCC and its more aggressive biologic behavior.
Effect of UV and UV–Ozone Treatment of Polyolefin Fibers on Toughness of Fiber Concrete Composite
Authors: Payrow Pouria , Nokken Michelle R. , Banu Dorina , Schmidt Rolf , DeWolf Christine E. , Feldman Dorel 
Published: March 2013

Abstract
Ultraviolet (UV) irradiation and a combination of UV irradiation and ozone treatment of polyolefin fibers were investigated for possible improvement of mechanical properties in concrete composites. In both treatment methods, various fiber exposure durations were used, and surface modification was monitored by measuring the water contact angle. Untreated and treated fibers were added to concrete at 0.32 % by volume, and the specimens were tested for flexural strength according to ASTM International specifications. Fiber surface treatment by UV alone was found to be an unattractive technique based on the results of flexural tests and contact angle measurements. Ten minutes of UV and ozone surface treatment of fibers was found to improve the composite peak stress by 11 % and the toughness by 4 %; longer periods of exposure led to lower flexural strength results, perhaps as a result of fiber deformation or degradation.
Workability and Setting Time of Alkali Activated Blast Furnace Slag Paste
Authors: Qureshi Mohd. Nadeem , Ghosh Somnath 
Published: March 2013

Abstract
This paper reports the results of an experimental investigation of blast furnace slag paste activated by potassium hydroxide and sodium silicate. Reasonable workability and setting times were maintained. The workability was measured in terms of flow diameter. The loss of flow with time was also studied. The major parameters studied were water/binder ratio, alkali content, silicate content, slag/activator ratio, silicate modulus, and sodium silicate/potassium hydroxide ratio, and their effects on workability and setting time are presented. It was found that the workability and setting time of alkali activated ground granulated blast furnace slag paste are dependent basically on the alkali content, silicate content, and silicate modulus. Locally available blast furnace slag has been utilized, and its potential as source material has been verified. This information will be useful to manufacturers and researchers.
Histology and immunohistochemistry of the parathyroid glands in renal secondary hyperparathyroidism refractory to vitamin D or cinacalcet therapy
Authors: Vulpio Carlo , Bossola Maurizio , Di Stasio Enrico , Tazza Luigi , Silvestri Patrizia , Fadda Guido 
Published: March 2013

BackgroundCinacalcet is a new effective treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients (HP), but the alterations of parathyroid gland (PTG) hyperplasia determined by cinacalcet and vitamin D have not been extensively investigated in humans.MethodsWe performed histological analyses of 94 PTGs removed from 25 HP who underwent parathyroidectomy (PTx) because of SHPT refractory to therapy with vitamin D alone (group A=13 HP and 46 PTGs) or associated with cinacalcet (group B=12 HP and 48 PTGs). The number, weight, the macroscopic cystic/hemorrhagic changes, and type of hyperplasia of PTG (nodular=NH, diffuse=DH) were assessed. In randomly selected HP of group A (4 HP and 14 PTGs) and group B (4 HP and 15 PTGs), the labeling index of cells positive to Ki-67 and TUNEL and the semiquantitative score of immunohistochemistry staining of vitamin D receptor, calcium-sensing receptor, and vascular endothelial growth factor-α (VEGF-α) were measured in the entire PTGs and in the areas with DH or NH.ResultsThe number and weight of single and total PTG of each HP were similar in the two groups as well as the number of PTG with macroscopic cystic/hemorrhagic areas. TUNEL, Ki-67, and VEGF-α scores were higher in NH than in DH areas.ConclusionThis observational study of a highly selected population of HP, submitted to PTx because SHPT refractory to therapy, shows that the macroscopic, microscopic, and immunochemistry characteristics of PTG in HP who received or did not receive cinacalcet before PTx did not differ significantly.
Quality of life in adults with congenital adrenal hyperplasia relates to glucocorticoid treatment, adiposity and insulin resistance: United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE)
Authors: Han Thang S , Krone Nils , Willis Debbie S , Conway Gerard S , Hahner Stefanie , Rees D Aled , Stimson Roland H , Walker Brian R , Arlt Wiebke , Ross Richard J , _ _ 
Published: March 2013

ContextQuality of life (QoL) has been variously reported as normal or impaired in adults with congenital adrenal hyperplasia (CAH). To explore the reasons for this discrepancy we investigated the relationship between QoL, glucocorticoid treatment and other health outcomes in CAH adults.MethodsCross-sectional analysis of 151 adults with 21-hydroxylase deficiency aged 18–69 years in whom QoL (assessed using the Short Form Health Survey), glucocorticoid regimen, anthropometric and metabolic measures were recorded. Relationships were examined between QoL, type of glucocorticoid (hydrocortisone, prednisolone and dexamethasone) and dose of glucocorticoid expressed as prednisolone dose equivalent (PreDEq). QoL was expressed as z-scores calculated from matched controls (14 430 subjects from UK population). Principal components analysis (PCA) was undertaken to identify clusters of associated clinical and biochemical features and the principal component (PC) scores used in regression analysis as predictor of QoL.ResultsQoL scores were associated with type of glucocorticoid treatment for vitality (P=0.002) and mental health (P=0.011), with higher z-scores indicating better QoL in patients on hydrocortisone monotherapy (P<0.05). QoL did not relate to PreDEq or mutation severity. PCA identified three PCs (PC1, disease control; PC2, adiposity and insulin resistance and PC3, blood pressure and mutations) that explained 61% of the variance in observed variables. Stepwise multiple regression analysis demonstrated that PC2, reflecting adiposity and insulin resistance (waist circumference, serum triglycerides, homeostasis model assessment of insulin resistance and HDL-cholesterol), related to QoL scores, specifically impaired physical functioning, bodily pain, general health, Physical Component Summary Score (P<0.001) and vitality (P=0.002).ConclusionsIncreased adiposity, insulin resistance and use of prednisolone or dexamethasone are associated with impaired QoL in adults with CAH. Intervention trials are required to establish whether choice of glucocorticoid treatment and/or weight loss can improve QoL in CAH adults.
A Novel Role of the N Terminus of Budding Yeast Histone H3 Variant Cse4 in Ubiquitin-Mediated Proteolysis
Authors: Au Wei Chun , Dawson Anthony R , Rawson David W , Taylor Sara B , Baker Richard E , Basrai Munira A 
Published: March 2013

Abstract
Regulating levels of centromeric histone H3 (CenH3) variant is crucial for genome stability. Interaction of Psh1, an E3 ligase, with the C terminus of Cse4 has been shown to contribute to its proteolysis. Here, we demonstrate a role for ubiquitination of the N terminus of Cse4 in regulating Cse4 proteolysis for faithful chromosome segregation and a role for Doa1 in ubiquitination of Cse4.
Natural Gas Reciprocating Compressor Optimization
Authors: Mino Jean 
Published: March 2013

Abstract
The compressor is the heartbeat of the natural gas pipeline system. Regardless of natural gas price, it is imperative that compressors, irrespective of purpose, remain operating in their most optimized state. The definition of "optimized" might be different for the spectrum of owners / operators in the natural gas industry. "Optimized" can imply any arrangement of maximum throughput, fuel efficiency, reliability, constant suction pressure, or availability; depending on the priority and array of the compressor's owner, operator, operating conditions and working requirements. However, for any particular combination of suction and discharge pressures, every compressor has a specific loading profile in which every horsepower available can be utilized as efficiently as possible. Additionally, considering today's ever-tightening environmental standards, optimized compressor operation translates to lower emissions.