bluuebunny/crossref_metadata_2025_split huggingface dataset:
The
Neisseria gonorrhoeae
Biofilm Matrix Contains DNA, and an Endogenous Nuclease Controls Its Incorporation
Authors: Steichen Christopher T. , Cho Christine , Shao Jian Q. , Apicella Michael A. 
Published: February 2011

ABSTRACT

Neisseria gonorrhoeae
has been shown to produce biofilms both in experimental flow chambers and in the human host. Our laboratory has shown that extracellular DNA is an essential component of the gonococcal matrix. We have also identified a gene in
N. gonorrhoeae
, which we designated
nuc
. This gene has homology with the staphylococcus-secreted thermonuclease. Our laboratory has characterized
nuc
through phenotypic analysis of a
nuc
deletion mutant. Biofilms grown with this strain are significantly thicker and of greater biomass than the
N. gonorrhoeae
1291 parent strain. Confocal microscopy indicates that the increased size of the mutant biofilms appears to be due to elevated amounts of extracellular DNA in the biofilm matrix. Chromosomal complementation of the
nuc
mutation restored the wild-type biofilm phenotype. In addition, we have cloned and expressed the Nuc protein in
Escherichia coli
, and our data indicate that it has the ability to digest multiple forms of DNA and is a thermonuclease. The ability of Nuc to digest DNA also extends to its ability to disrupt established gonococcal biofilms through degradation of the DNA in the biofilm matrix. Our studies indicate that the
N. gonorrhoeae
biofilm contains DNA and that the Nuc protein appears to play a role in biofilm formation and remodeling.
Republished review: Tourette's syndrome and other tic disorders
Authors: Rickards Hugh 
Published: February 2011

ABSTRACT
Tourette's syndrome is a neuropsychiatric disorder characterised by motor and phonic tics. Although tics are common in children, only about 1% of those affected meet the criteria for Tourette's syndrome, and many are not disabled by it. Associated problems such as attention deficit hyperactivity disorder and obsessive–compulsive disorders can often be more disabling than the tics themselves. People with Tourette's tend to be worst in their teenage years but improve in adulthood. The cause is unknown but there are strong genetic factors. Treatment should be aimed at minimising disability and includes social, psychological and biological approaches.
Environmental review of geyser basins: resources, scarcity, threats, and benefits
Authors: Barrick Kenneth A. 
Published: February 2011

The world’s geysers are known for providing one of nature’s most unusual water spectacles, with most sending water upwards of about 3 m, but a few “grand” or tall geysers erupt to heights of 60 m or more. A geyser basin is a composite resource made up of geysers and hot springs that cluster around a common hydrothermal reservoir, and might also contain other hydrothermal features like fumaroles and mud pots. The world’s remaining geyser basins are exceptionally rare, and are increasingly important recreation, economic, scientific, cultural, spiritual, therapeutic, and national heritage assets. Geyser basins harbor thermophilic microorganisms that contain heat-adapted biomolecules that can be harvested to provide vital components for DNA testing, and other high-temperature industrial processes. However, geysers and other surface hydrothermal features are increasingly vulnerable, and can be quickly and irreversibly damaged. Energy development projects quenched about 249 geysers, or about half of all geysers that were not protected in a national park or reserve. About 100 geysers were driven to extinction in New Zealand, about 46 in Iceland, and about 48 in the USA. Sustaining the world’s remaining geyser basins requires protecting the hydrothermal reservoirs that support them based on an integrated management approach that takes into account the distinctive characteristics of surface hydrothermal features and the benefits that society derives from them. A framework is provided that defines geyser basin resources, the scarcity of the remaining geysers, the environmental threats, and preservation benefits. Multiple case studies of mass geyser extinction are highlighted, including a summary of the landscape changes that can accompany geothermal energy development.
VarInt
Authors: Hellström Christian 
Published: February 2011

Geometric numerical integration refers to a class of numerical integration algorithms that preserve the differential geometric structure that defines the evolution of dynamical systems. For simulations over relatively short time spans, as compared to the intrinsic time scales, standard (non-geometric) integrators are often advantageous, as they include adaptive and multistep methods, which can be both accurate and fast. Extended computations require a different, geometric approach, as non-geometric methods tend to generate or dissipate energy artificially due to the fact that they do not respect the fundamental geometry of the phase flow, which means that at some point the errors dominate.
It is common to create geometric numerical integrators based on either previous knowledge of classes of non-geometric numerical integrators, from which specific instances can be derived that are geometric, or truncated series solutions to the Hamilton--Jacobi equation for (canonical) transformations near the identity. Unfortunately, the actual calculations for higher-order geometric numerical algorithms are generally quite involved.
There is, however, an alternative strategy that avoids many of the difficulties inherent in the design of higher-order versions of these geometric numerical integrators. It relies on the discretization of the action functional, from which one derives the numerical algorithms in a straightforward manner. These so-called variational integrators preserve the differential geometric structure automatically; all conserved quantities are preserved infinitesimally, too.
An easy-to-use and freely available package named VarInt is presented that enables one to generate and analyse new variational integrators systematically to arbitrary order with Maple. All VarInt requires from the user is the action and a quadrature formula to approximate it. One can either select one of the built-in quadrature rules, or one supplies it manually. With VarInt it is now possible to venture beyond the standard geometric numerical integrators, without the need for an advanced appreciation of the mathematical details. Several numerical examples, obtained with a basic numerical analysis tool in VarInt, demonstrate the superior performance of new variational integrators for certain classes of dynamical systems.
VarInt is ideally suited for researchers and engineers who wish to design, study, test and/or analyse new geometric numerical integration algorithms without the hassle of laborious computations. All algorithms can be tuned to the required level of specificness of the problem at hand due to Maples symbolic capabilities and its code optimization procedures. In addition, VarInt can be of value in the classroom, as a tool to assist in increasing the understanding of variational integrators.
A New Hybrid Algorithm for a System of Mixed Equilibrium Problems, Fixed Point Problems for Nonexpansive Semigroup, and Variational Inclusion Problem
Authors: Jitpeera Thanyarat , Kumam Poom 
Published: February 2011

AbstractThe purpose of this paper is to consider a shrinking projection method for finding the common element of the set of common fixed points for nonexpansive semigroups, the set of common fixed points for an infinite family of a "Equation missing"-strict pseudocontraction, the set of solutions of a system of mixed equilibrium problems, and the set of solutions of the variational inclusion problem. Strong convergence of the sequences generated by the proposed iterative scheme is obtained. The results presented in this paper extend and improve some well-known results in the literature.
MRE11 Deficiency Increases Sensitivity to Poly(ADP-ribose) Polymerase Inhibition in Microsatellite Unstable Colorectal Cancers
Authors: Vilar Eduardo , Bartnik Catherine M. , Stenzel Stephanie L. , Raskin Leon , Ahn Jaeil , Moreno Victor , Mukherjee Bhramar , Iniesta Maria D. , Morgan Meredith A. , Rennert Gad , Gruber Stephen B. 
Published: February 2011

Abstract
Microsatellite instability (MSI) is displayed by approximately 15% of colorectal cancers (CRC). Defective DNA mismatch repair generates mutations at repetitive DNA sequences such as those located in the double strand break (DSB) repair gene MRE11. We assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in MRE11 may sensitize CRC cells to poly(ADP-ribose) polymerase (PARP-1) inhibition based on the concept of synthetic lethality. We further assessed the activity of the PARP-1 inhibitor, ABT-888, in CRC cell lines and observed preferential cytotoxicity in those MSI cell lines harboring mutations in MRE11 compared with both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between MRE11 expression levels and cytotoxicity to ABT-888 at 10 μM was observed (R2 = 0.915, P &lt; 0.001). Using two experimental approaches, including short hairpin RNA knocking down MRE11 in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant MRE11, we experimentally tried to confirm the role of MRE11 in conferring sensitivity to PARP-1 inhibition. Both models led to changes in proliferation in response to ABT-888 at different concentrations, and a drug–response effect was not observed, suggesting a possible contribution of additional genes. We conclude that MSI colorectal tumors deficient in DSB repair secondary to mutation in MRE11 show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs. Cancer Res; 71(7); 2632–42. ©2011 AACR.
The Efficacy of Radiotherapy Relies upon Induction of Type I Interferon–Dependent Innate and Adaptive Immunity
Authors: Burnette Byron C. , Liang Hua , Lee Youjin , Chlewicki Lukasz , Khodarev Nikolai N. , Weichselbaum Ralph R. , Fu Yang-Xin , Auh Sogyong L. 
Published: February 2011

Abstract
The most widely held explanation for the efficacy of local radiotherapy (RT) is based on direct cytotoxicity to cancer cells through the induction of lethal DNA damage. Recent studies have shown that local ablative radiation of established tumors can lead to increased T-cell priming and T-cell–dependent tumor regression, but the underlying mechanism remains unclear. Here, we describe an essential role for type I IFN in local RT-mediated tumor control. We show that ablative RT increases intratumoral production of IFN-β and, more surprisingly, the antitumor effect of RT is abolished in type I IFN nonresponsive hosts. Furthermore, the major target of RT-induced type I IFN is the hematopoietic compartment. RT drastically enhances the cross-priming capacity of tumor-infiltrating dendritic cells (TIDC) from wild-type mice but not type I IFN receptor–deficient mice. The enhanced cross-priming ability of TIDCs after RT was dependent on autocrine production of type I IFNs. By using adenoviral-mediated expression of IFN-β, we show that delivery of exogenous IFN-β into the tumor tissue in the absence of RT is also sufficient to selectively expand antigen-specific T cells leading to complete tumor regression. Our study reveals that local high-dose RT can trigger production of type I IFN that initiates a cascading innate and adaptive immune attack on the tumor. Cancer Res; 71(7); 2488–96. ©2011 AACR.
Lactate Influx through the Endothelial Cell Monocarboxylate Transporter MCT1 Supports an NF-κB/IL-8 Pathway that Drives Tumor Angiogenesis
Authors: Végran Frédérique , Boidot Romain , Michiels Carine , Sonveaux Pierre , Feron Olivier 
Published: February 2011

AbstractLactate generated from pyruvate fuels production of intracellular NAD+ as an end result of the glycolytic process in tumors. Elevated lactate concentration represents a good indicator of the metabolic adaptation of tumors and is actually correlated to clinical outcome in a variety of human cancers. In this study, we investigated whether lactate could directly modulate the endothelial phenotype and thereby tumor vascular morphogenesis and perfusion. We found that lactate could enter endothelial cells through the monocarboxylate transporter MCT-1, trigger the phosphorylation/degradation of IκBα, and then stimulate an autocrine NF-κB/IL-8 (CXCL8) pathway driving cell migration and tube formation. These effects were prevented by 2-oxoglutarate and reactive oxygen species (ROS) inhibitors, pointing to a role for prolyl-hydroxylase and ROS in the integration of lactate signaling in endothelial cells. PHD2 silencing in endothelial cells recapitulated the proangiogenic effects of lactate, whereas a blocking IL-8 antibody or IL-8–targeting siRNA prevented them. Finally, we documented in mouse xenograft models of human colorectal and breast cancer that lactate release from tumor cells through the MCT4 (and not MCT1) transporter is sufficient to stimulate IL-8–dependent angiogenesis and tumor growth. In conclusion, our findings establish a signaling role for lactate in endothelial cells and they identify the lactate/NF-κB/IL-8 pathway as an important link between tumor metabolism and angiogenesis. Cancer Res; 71(7); 2550–60. ©2011 AACR.
Can a Metastatic Gene Expression Profile Outperform Tumor Size as a Predictor of Occult Lymph Node Metastasis in Oral Cancer Patients?
Authors: Méndez Eduardo , Lohavanichbutr Pawadee , Fan Wenhong , Houck John R. , Rue Tessa C. , Doody David R. , Futran Neal D. , Upton Melissa P. , Yueh Bevan , Zhao Lue Ping , Schwartz Stephen M. , Chen Chu 
Published: February 2011

Abstract
Purpose: To determine the differential gene expression between oral squamous cell carcinoma (OSCC) with and without metastasis to cervical lymph nodes and to assess prediction of nodal metastasis by using molecular features.
Experimental Design: We used Affymetrix U133 2.0 plus arrays to compare the tumor genome-wide gene expression of 73 node-positive OSCCs with 40 node-negative OSCCs (≥18 months). Multivariate linear regression was used to estimate the association between gene expression and nodal metastasis. Stepwise logistic regression and receiver operating characteristics (ROC) analysis were used to generate predictive models and to compare these with models by using tumor size alone.
Results: We identified five genes differentially expressed between node-positive and node-negative OSCCs after adjusting for tumor size and human papillomavirus status: REEP1, RNF145, CTONG2002744, MYO5A, and FBXO32. Stepwise regression identified a four-gene model (MYO5A, RFN145, FBXO32, and CTONG2002744) as the most predictive of nodal metastasis. A leave-one-out ROC analysis revealed that our model had a higher area under the curve (AUC) for identifying occult nodal metastasis compared with that of a model by tumor size alone (respective AUC: 0.85 and 0.61; P = 0.011). A model combining tumor size and gene expression did not further improve the prediction of occult metastasis. Independent validation using 31 metastatic and 13 nonmetastatic cases revealed a significant underexpression of CTONG2002744 (P = 0.0004).
Conclusions: These results suggest that our gene expression markers of OSCC metastasis hold promise for improving current clinical practice. Confirmation by others and functional studies of CTONG2002744 is warranted. Clin Cancer Res; 17(8); 2466–73. ©2011 AACR.
EGFRL858R Mutation and Polymorphisms of Genes Related to Estrogen Biosynthesis and Metabolism in Never-Smoking Female Lung Adenocarcinoma Patients
Authors: Yang Shi-Yi , Yang Tsung-Ying , Chen Kun-Chieh , Li Yao-Jen , Hsu Kuo-Hsuan , Tsai Chi-Rne , Chen Chih-Yi , Hsu Chung-Ping , Hsia Jiun-Yi , Chuang Cheng-Yen , Tsai Ying-Huang , Chen Kuan-Yu , Huang Ming-Shyan , Su Wu-Chou , Chen Yuh-Min , Hsiung Chao A. , Shen Chen-Yang , Chang Gee-Chen , Yang Pan-Chyr , Chen Chien-Jen 
Published: February 2011

AbstractPurpose: To assess whether polymorphisms of genes related to estrogen biosynthesis and metabolism are associated with EGFR mutations.Experimental Design: We studied 617 patients with lung adenocarcinoma, including 302 never-smoking women. On the basis of multiple candidate genes approach, the effects of polymorphisms of CYP17, CYP19A1, ERα, and COMT in association with the occurrence of EGFR mutations were evaluated using logistic regression analysis.Results: In female never-smokers, significant associations with EGFR L858R mutation were found for the tetranucleotide (TTTA)n repeats in CYP19A1 (odds ratio, 2.6; 95%CI, 1.2–5.7 for 1 or 2 alleles with (TTTA)n repeats &gt;7 compared with both alleles with (TTTA)n repeats ≤7), and the rs2234693 in ERα (OR, 2.1; 95% CI, 1.1–4.0 for C/T and C/C genotypes compared with T/T genotype). The C/C genotype (vs. T/T genotype) of ERα was significantly associated with EGFR L858R mutation (OR, 3.0; 95% CI, 1.1–8.1), in-frame deletion (OR, 2.9; 95% CI, 1.1–7.6) and other mutations (OR, 4.3; 95% CI, 1.3–14.0). The genotype of COMT rs4680 was significantly associated with EGFR L858R mutation in female and male never-smokers showing OR's (95% CI) of 1.8 (1.0–3.2) and 3.6 (1.1–11.3), respectively, for genotypes G/A and G/G compared with genotype A/A. The number of risk alleles of CYP17, CYP19A1, ERα, and COMT was associated with an increasing OR of EGFR L858R mutation in female never-smokers (P = 0.0002 for trend).Conclusions: The L858R mutation of EGFR is associated with polymorphisms of genes related to estrogen biosynthesis and metabolism in never-smoking female lung adenocarcinoma patients. Clin Cancer Res; 17(8); 2149–58. ©2011 AACR.
Pharmacokinetics of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors: the Role of Alpha-1-Acid Glycoprotein Binding
Authors: Graham Richard A. , Lum Bert L. , Cheeti Sravanthi , Jin Jin Yan , Jorga Karin , Von Hoff Daniel D. , Rudin Charles M. , Reddy Josina C. , Low Jennifer A. , LoRusso Patricia M. 
Published: February 2011

Abstract
Purpose: In a phase I trial for patients with refractory solid tumors, hedgehog pathway inhibitor vismodegib (GDC-0449) showed little decline in plasma concentrations over 7 days after a single oral dose and nonlinearity with respect to dose and time after single and multiple dosing. We studied the role of GDC-0449 binding to plasma protein alpha-1-acid glycoprotein (AAG) to better understand these unusual pharmacokinetics.
Experimental Design: Sixty-eight patients received GDC-0449 at 150 (n = 41), 270 (n = 23), or 540 (n = 4) mg/d, with pharmacokinetic (PK) sampling at multiple time points. Total and unbound (dialyzed) GDC-0449 plasma concentrations were assessed by liquid chromatography/tandem mass spectrometry, binding kinetics by surface plasmon resonance–based microsensor, and AAG levels by ELISA.
Results: A linear relationship between total GDC-0449 and AAG plasma concentrations was observed across dose groups (R2 = 0.73). In several patients, GDC-0449 levels varied with fluctuations in AAG levels over time. Steady-state, unbound GDC-0449 levels were less than 1% of total, independent of dose or total plasma concentration. In vitro, GDC-0449 binds AAG strongly and reversibly (KD = 13 μmol/L) and human serum albumin less strongly (KD = 120 μmol/L). Simulations from a derived mechanistic PK model suggest that GDC-0449 pharmacokinetics are mediated by AAG binding, solubility-limited absorption, and slow metabolic elimination.
Conclusions: GDC-0449 levels strongly correlated with AAG levels, showing parallel fluctuations of AAG and total drug over time and consistently low, unbound drug levels, different from previously reported AAG-binding drugs. This PK profile is due to high-affinity, reversible binding to AAG and binding to albumin, in addition to solubility-limited absorption and slow metabolic elimination properties. Clin Cancer Res; 17(8); 2512–20. ©2011 AACR.
A novel missense mutation in the FGB g. 3354 T>A (p. Y41N), Fibrinogen Caracas VIII
Authors: Rojas Héctor , Meyer Michael , Castillo Oscar , Sáez Ruiz Arlette De , Weisel John , Marchi Rita 
Published: February 2011

SummaryA novel dysfibrinogenaemia with a replacement of Tyr by Asn at Bβ41 has been discovered (fibrinogen Caracas VIII). An asymptomatic 39-year-old male was diagnosed as having dysfibrinogenaemia due to a mildly prolonged thrombin time (+ 5.8 seconds); his fibrinogen concentration was in the low normal range, both by Clauss and gravimetric determination, 1.9 g/l and 2.1 g/l, respectively. The plasma polymerization process was slightly impaired, characterised by a mildly prolonged lag time and a slightly increased final turbidity. Permeation through the patients´ clots was dramatically increased, with the Darcy constant around four times greater than that of the control (22 ± 2 x10–9 cm2 compared to 6 ± 0.5 x10–9 cm2 in controls). The plasma fibrin structure of the patient, by scanning electron microscopy, featured a mesh composed of thick fibres (148 ± 50 nm vs. 120 ± 31 nm in controls, p<0.05) and larger pores than those of the control fibrin clot. The viscoelastic properties of the clot from the patient were also altered, as the storage modulus (G‘, 310 ± 30) was much lower than in the control (831 ± 111) (p ≤0.005). The interaction of the fibrin clot with a monolayer of human microvascular endothelial cells, by confocal laser microscopy, revealed that the patients´ fibrin network had less interaction with the cells. These results demonstrate the significance of the amino terminal end of the β chain of fibrin in the polymerisation process and its consequences on the clot organisation on the surface of endothelial cells.
Frequency of Platelet type versus Type 2B von Willebrand Disease
Authors: Hamilton Alexander , Ozelo Margareth , Leggo Jayne , Notley Colleen , Brown Hannah , Pablo Frontroth Juan , Angelillo-Scherrer Anne , Baghaei Fariba , Enayat Said , Favaloro Emmanuel , Lillicrap David , Othman Maha 
Published: February 2011

SummaryLess than 50 patients are reported with platelet type von Willebrand disease (PT-VWD) worldwide. Several reports have discussed the diagnostic challenge of this disease versus the closely similar disorder type 2B VWD. However, no systematic study has evaluated this dilemma globally. Over three years, a total of 110 samples/data from eight countries were analysed. A molecular approach was utilised, analysing exon 28 of the von Willebrand factor (VWF) gene, and in mutation negative cases the platelet GP1BA gene. Our results show that 48 cases initially diagnosed as putative type 2B/PT-VWD carried exon 28 mutations consistent with type 2B VWD, 17 carried GP1BA mutations consistent with a PT-VWD diagnosis, three had other VWD types (2A and 2M) and five expressed three non-previously published exon 28 mutations. Excluding 10 unaffected family members and one acquired VWD, 26 cases did not have mutations in either genes. Based on our study, the percentage of type 2B VWD diagnosis is 44% while the percentage of misdiagnosis of PT-VWD is 15%. This is the first large international study to investigate the occurrence of PT-VWD and type 2B VWD worldwide and to evaluate DNA analysis as a diagnostic tool for a large cohort of patients. The study highlights the diagnostic limitations due to unavailability/poor application of RIPA and related tests in some centres and proposes genetic analysis as a suitable tool for the discrimination of the two disorders worldwide. Cases that are negative for both VWF and GP1BA gene mutations require further evaluation for alternative diagnoses.