bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Ganciclovir during Continuous Venovenous Hemodiafiltration in Critically Ill Patients
Authors: Horvatits Thomas , Kitzberger Reinhard , Drolz Andreas , Zauner Christian , Jäger Walter , Böhmdorfer Michaela , Kraff Stefanie , Fritsch Achim , Thalhammer Florian , Fuhrmann Valentin , Schenk Peter 
Published: October 2013

ABSTRACT
Ganciclovir is an antiviral agent that is frequently used in critically ill patients with cytomegalovirus (CMV) infections. Continuous venovenous hemodiafiltration (CVVHDF) is a common extracorporeal renal replacement therapy in intensive care unit patients. The aim of this study was to investigate the pharmacokinetics of ganciclovir in anuric patients undergoing CVVHDF. Population pharmacokinetic analysis was performed for nine critically ill patients with proven or suspected CMV infection who were undergoing CVVHDF. All patients received a single dose of ganciclovir at 5 mg/kg of body weight intravenously. Serum and ultradiafiltrate concentrations were assessed by high-performance liquid chromatography, and these data were used for pharmacokinetic analysis. Mean peak and trough prefilter ganciclovir concentrations were 11.8 ± 3.5 mg/liter and 2.4 ± 0.7 mg/liter, respectively. The pharmacokinetic parameters elimination half-life (24.2 ± 7.6 h), volume of distribution (81.2 ± 38.3 liters), sieving coefficient (0.76 ± 0.1), total clearance (2.7 ± 1.2 liters/h), and clearance of CVVHDF (1.5 ± 0.2 liters/h) were determined. Based on population pharmacokinetic simulations with respect to a target area under the curve (AUC) of 50 mg · h/liter and a trough level of 2 mg/liter, a ganciclovir dose of 2.5 mg/kg once daily seems to be adequate for anuric critically ill patients during CVVHDF.
Monotherapy with Fluoroquinolone or Trimethoprim-Sulfamethoxazole for Treatment of Stenotrophomonas maltophilia Infections
Authors: Wang Yu Lin , Scipione Marco R. , Dubrovskaya Yanina , Papadopoulos John 
Published: October 2013

ABSTRACTThe treatment of choice forStenotrophomonas maltophiliais trimethoprim-sulfamethoxazole (SXT). Fluoroquinolones (FQs) havein vitroactivity againstS. maltophilia; however, there is limited published information on their effectiveness. The purpose of this study is to compare the effectiveness of FQs and SXT for the treatment ofS. maltophilia. A retrospective review of 98 patients withS. maltophiliainfections who received SXT or FQ monotherapy was conducted. Patients ≥18 years old with a positive culture forS. maltophiliaand clinical signs of infection who received treatment for ≥48 h were included. Microbiological cure and clinical response were evaluated at the end of therapy (EOT). In-hospital mortality and isolation of nonsusceptible isolates were also evaluated. Thirty-five patients received SXT, and 63 patients received FQ; 48 patients received levofloxacin, and 15 patients received ciprofloxacin. The most common infection was pulmonary. The overall microbiological cure rate at EOT was 63%. Thirteen of 20 patients (65%) who received SXT and 23 of 37 patients (62%) who received FQ had microbiological cure at EOT (P= 0.832). The overall clinical success rate was 55%, 52% for those who received FQ and 61% for those who received SXT (P= 0.451). In-hospital mortality was 24%, with similar rates in the two groups (25% for FQ versus 22% for SXT;P= 0.546). Development of resistance on repeat culture was 30% for FQ and 20% for SXT (P= 0.426). Fluoroquinolone and SXT monotherapies may be equally effective for the treatment ofS. maltophiliainfections. Resistance was documented in subsequent isolates ofS. maltophiliain both groups.
Distribution of Hydroxychloroquine in Lymphoid Tissue in a Rabbit Model for HIV Infection
Authors: González-Hernández Iliana , Aguirre-Cruz Lucinda , Sotelo Julio , López-Arellano Raquel , Morales-Hipólito Adriana , Jung-Cook Helgi 
Published: October 2013

ABSTRACT
Hydroxychloroquine has been proposed for HIV treatment; however, little is known about its disposition in the lymphatic system, where replication takes place. Therefore, its distribution in lymphoid tissues (Peyer's patches and popliteal, submandibular, femoral, splenic, and prescapular lymph nodes) was evaluated and compared with that in blood. Results showed a high affinity of hydroxychloroquine for all of these tissues, with higher affinity for the splenic and submandibular lymph nodes, suggesting its potential use as a coadjuvant in HIV therapy.
Novel Antifungal Drug Discovery Based on Targeting Pathways Regulating the Fungus-Conserved Upc2 Transcription Factor
Authors: Gallo-Ebert Christina , Donigan Melissa , Stroke Ilana L. , Swanson Robert N. , Manners Melissa T. , Francisco Jamie , Toner Geoffrey , Gallagher Denise , Huang Chia-Yu , Gygax Scott E. , Webb Maria , Nickels Joseph T. 
Published: October 2013

ABSTRACT

Infections by
Candida albicans
and related fungal pathogens pose a serious health problem for immunocompromised patients. Azole drugs, the most common agents used to combat infections, target the sterol biosynthetic pathway. Adaptation to azole therapy develops as drug-stressed cells compensate by upregulating several genes in the pathway, a process mediated in part by the Upc2 transcription factor. We have implemented a cell-based high-throughput screen to identify small-molecule inhibitors of Upc2-dependent induction of sterol gene expression in response to azole drug treatment. The assay is designed to identify not only Upc2 DNA binding inhibitors but also compounds impeding the activation of gene expression by Upc2. An AlphaScreen assay was developed to determine whether the compounds identified interact directly with Upc2 and inhibit DNA binding. Three compounds identified by the cell-based assay inhibited Upc2 protein level and
UPC2-LacZ
gene expression in response to a block in sterol biosynthesis. The compounds were growth inhibitory and attenuated antifungal-induced sterol gene expression
in vivo
. They did so by reducing the level of Upc2 protein and Upc2 DNA binding in the presence of drug. The mechanism by which the compounds restrict Upc2 DNA binding is not through a direct interaction, as demonstrated by a lack of DNA binding inhibitory activity using the AlphaScreen assay. Rather, they likely inhibit a novel pathway activating Upc2 in response to a block in sterol biosynthesis. We suggest that the compounds identified represent potential precursors for the synthesis of novel antifungal drugs.
Pharmacometric Characterization of Efavirenz Developmental Pharmacokinetics and Pharmacogenetics in HIV-Infected Children
Authors: Salem Ahmed Hamed , Fletcher Courtney V. , Brundage Richard C. 
Published: October 2013

ABSTRACTThe aim of this analysis was to create a pharmacometric model of efavirenz developmental pharmacokinetics and pharmacogenetics in HIV-infected children. The data consisted of 3,172 plasma concentrations from 96 HIV-1-infected children who participated in the Pediatric AIDS Clinical Trials Group 382 (PACTG382) study. Analyses were performed using NONMEM, and the impacts of body weight, age, race, sex, formulation, liver function, and cytochrome P450 2B6 (CYP2B6)-G516T and multidrug-resistance transporter gene (MDR1)-C3435T polymorphisms were assessed. A one-compartment model using weight-based allometry on oral clearance and apparent volume of distribution adequately described the data. A sigmoid maximum-effect (Emax) maturation model demonstrated an increase in oral clearance with age to reach 90% of its mature level by the age of 9 months. The liquid formulation bioavailability relative to the capsule was found to increase with age to reach 90% of its mature value by the age of 8 years. The CYP2B6-G516T polymorphism decreased oral clearance, while the MDR1-C3435T polymorphism demonstrated no effect.
Introduction
Authors: Lucas S.B. , St-Onge M.R. , Percival J.A. 
Published: October 2013

Abstract
The Canadian Shield contains a remarkable and extensive record of the Earth's Precambrian geology and tectonic history (Hoffman, 1989). It spans from the oldest known rocks on Earth (Acasta gneiss complex, Slave Province, Fig. 1.1, see colour section; King, 1985; Bowring et al., 1989; Stern and Bleeker, 1998) to the world's largest Archean craton, the Superior Province (Fig. 1.1; Card and Poulsen, Chapter 2, this volume). One of the hallmarks of the Canadian Shield is the network of Paleoproterozoic orogenic belts (Fig. 1.1; Map 1860A, in pocket) that stitched together Laurentia at 2.0-1.8 Ga, and which were systematically described by Hoffman (1988) in a landmark paper entitled “United plates of America, the birth of a craton: Early Proterozoic assembly and growth of Laurentia” (see also Lewry and Collerson, 1990; Ross et al., 1991, 1995; St-Onge et al., 1992, 1997, in press; Lucas et al., 1993, 1996a; Lewry et al., 1994; White et al., 1994, in press; Hall et al., 1995; Van Kranendonk and Wardle, 1996; Wardle and Van Kranendonk, 1996; Scott, 1998). It was in the study of the Paleoproterozoic orogens that the plate tectonic paradigm was first applied to Precambrian rocks (Hoffman, 1973; Dewey and Burke, 1973). These belts were subsequently shown to contain ophiolites (Scott et al., 1991, 1992), preserved intraoceanic accretionary collages (Lucas et al., 1996a), and mantle reflectors that outline paleosubduction zones (Cook et al., 1997). The Grenville Orogen (Fig. 1.1; Davidson, Chapter 3, this volume) and Mesoproterozoic basins (Map 1860A, in pocket) contain
An Overview of Grenville Province Geology, Canadian Shield
Authors: Davidson A. 
Published: October 2013

Abstract
The last major event that shaped the Canadian Shield, orogeny during the mid- to late Mesoproterozoic, left its imprint as a broad swath of highly deformed and metamorphosed rocks extending 2000 km from the Atlantic coast of southern Labrador to Lake Huron. The northwest margin of the resulting Grenville Province, referred to as the Grenville Front, is a zone of southeasterly dipping thrust faulting and mylonitization that truncates the various structural trends characterizing the adjacent, older shield provinces. Some 400–500 km farther southeast, the exhumed Grenville Province is overlain by lower Paleozoic platformal sedimentary rocks, but crystalline rocks bearing the imprint of Grenvillian orogenic events appear again in tectonic windows within the Appalachian Orogen of Maritime Canada and the eastern United States. Beyond its exposure in the Canadian Shield, the Grenville Orogen extends southwestward to Texas and Mexico; it is also recognized in inliers in the Caledonides of Northern Ireland, Scotland, and Norway, southeast of which it is represented by the Sveconorwegian Province of southern Norway and Sweden (Fig. 3.1). Recent reconstructions of supercontinent assembly in the early Neoproterozoic (e.g. Dalziel, 1991; Moores, 1991; Hoffman, 1991; Borg and DePaolo, 1994) show a further continuation of this belt from central America through Antarctica and eastern India to Australia.
The widely used term “Grenvillian Orogeny” embraces a range of tectonic events beginning with an early accretionary stage between ca. 1.3 and 1.2 Ga, and ending with uplift and exhumation shortly after 1.0 Ga. Arguing that the construction of orogens involves more than
Silencing of the miR-17∼92 Cluster Family Inhibits Medulloblastoma Progression
Authors: Murphy Brian L. , Obad Susanna , Bihannic Laure , Ayrault Olivier , Zindy Frederique , Kauppinen Sakari , Roussel Martine F. 
Published: October 2013

Abstract
Medulloblastoma, originating in the cerebellum, is the most common malignant brain tumor in children. Medulloblastoma consists of four major groups where constitutive activation of the Sonic Hedgehog (SHH) signaling pathway is a hallmark of one group. Mouse and human SHH medulloblastomas exhibit increased expression of microRNAs encoded by the miR-17∼92 and miR-106b∼25 clusters compared with granule progenitors and postmitotic granule neurons. Here, we assessed the therapeutic potential of 8-mer seed-targeting locked nucleic acid (LNA)-modified anti-miR oligonucleotides, termed tiny LNAs, that inhibit microRNA seed families expressed by miR-17∼92 and miR-106b∼25 in two mouse models of SHH medulloblastomas. We found that tumor cells (medulloblastoma cells) passively took up 8-mer LNA-anti-miRs and specifically inhibited targeted microRNA seed-sharing family members. Inhibition of miR-17 and miR-19a seed families by anti-miR-17 and anti-miR-19, respectively, resulted in diminished tumor cell proliferation in vitro. Treatment of mice with systemic delivery of anti-miR-17 and anti-miR-19 reduced tumor growth in flank and brain allografts in vivo and prolonged the survival of mice with intracranial transplants, suggesting that inhibition of the miR-17∼92 cluster family by 8-mer LNA-anti-miRs might be considered for the treatment of SHH medulloblastomas. Cancer Res; 73(23); 7068–78. ©2013 AACR.
BCCIP Suppresses Tumor Initiation but Is Required for Tumor Progression
Authors: Huang Yi-Yuan , Dai Li , Gaines Dakim , Droz-Rosario Roberto , Lu Huimei , Liu Jingmei , Shen Zhiyuan 
Published: October 2013

Abstract
Dysfunctions of genome caretaker genes contribute to genomic instability and tumor initiation. Because many of the caretaker genes are also essential for cell viability, permanent loss of function of these genes would prohibit further tumor progression. How essential caretaker genes contribute to tumorigenesis is not fully understood. Here, we report a “hit-and-run” mode of action for an essential caretaker gene in tumorigenesis. Using a BRCA2-interacting protein BCCIP as the platform, we found that a conditional BCCIP knockdown and concomitant p53 deletion caused rapid development of medulloblastomas, which bear a wide spectrum of alterations involving the Sonic Hedgehog (Shh) pathway, consistent with a caretaker responsibility of BCCIP on genomic integrity. Surprisingly, the progressed tumors have spontaneously lost the transgenic BCCIP knockdown cassette and restored BCCIP expression. Thus, a transient downregulation of BCCIP, but not necessarily a permanent mutation, is sufficient to initiate tumorigenesis. After the malignant transformation has been accomplished and autonomous cancer growth has been established, BCCIP reverses its role from a tumor-initiation suppressor to become a requisite for progression. This exemplifies a new type of tumor suppressor, which is distinct from the classical tumor suppressors that are often permanently abrogated during tumorigenesis. It has major implications on how a nonmutagenic or transient regulation of essential caretaker gene contributes to tumorigenesis. We further suggest that BCCIP represents a paradoxical class of modulators for tumorigenesis as a suppressor for initiation but a requisite for progression (SIRP). Cancer Res; 73(23); 7122–33. ©2013 AACR.
Misregulation of Pre-mRNA Alternative Splicing in Cancer
Authors: Zhang Jian , Manley James L. 
Published: October 2013

Abstract
Alternative splicing of mRNA precursors enables one gene to produce multiple protein isoforms with differing functions. Under normal conditions, this mechanism is tightly regulated in order for the human genome to generate proteomic diversity sufficient for the functional requirements of complex tissues. When deregulated, however, cancer cells take advantage of this mechanism to produce aberrant proteins with added, deleted, or altered functional domains that contribute to tumorigenesis. Here, we discuss aspects of alternative splicing misregulation in cancer, focusing on splicing events affected by deregulation of regulatory splicing factors and also recent studies identifying mutated components of the splicing machinery.
Significance: An increasing body of evidence indicates that aberrant splicing of mRNA precursors leads to production of aberrant proteins that contribute to tumorigenesis. Recent studies show that alterations in cellular concentrations of regulatory splicing factors and mutations in components of the core splicing machinery provide major mechanisms of misregulation of mRNA splicing in cancer. A better understanding of this misregulation will potentially reveal a group of novel drug targets for therapeutic intervention. Cancer Discov; 3(11); 1228–37. ©2013 AACR.
iNKT Cell Cytotoxic Responses Control T-Lymphoma GrowthIn VitroandIn Vivo
Authors: Bassiri Hamid , Das Rupali , Guan Peng , Barrett David M. , Brennan Patrick J. , Banerjee Pinaki P. , Wiener Susan J. , Orange Jordan S. , Brenner Michael B. , Grupp Stephan A. , Nichols Kim E. 
Published: October 2013

AbstractInvariant natural killer T (iNKT) cells comprise a lineage of CD1d-restricted glycolipid-reactive T lymphocytes with important roles in host immunity to cancer. iNKT cells indirectly participate in antitumor responses by inducing dendritic cell maturation and producing cytokines that promote tumor clearance by CD8+ T and NK cells. Although iNKT cells thereby act as potent cellular adjuvants, it is less clear whether they directly control the growth of tumors. To gain insights into the direct contribution of iNKT cells to tumor immune surveillance, we developed in vitro and in vivo systems to selectively examine the antitumor activity of iNKT cells in the absence of other cytolytic effectors. Using the EL4 T-lymphoma cell line as a model, we found that iNKT cells exert robust and specific lysis of tumor cells in vitro in a manner that is differentially induced by iNKT cell agonists of varying T-cell receptor (TCR) affinities, such as OCH, α-galactosyl ceramide, and PBS44. In vitro blockade of CD1d-mediated lipid antigen presentation, disruption of TCR signaling, or loss of perforin expression significantly reduce iNKT cell killing. Consistent with these findings, iNKT cell reconstitution of T, B, and NK cell–deficient mice slows EL4 growth in vivo via TCR-CD1d and perforin-dependent mechanisms. Together, these observations establish that iNKT cells are sufficient to control the growth of T lymphoma in vitro and in vivo. They also suggest that the induction of iNKT cell cytotoxic responses in situ might serve as a more effective strategy to prevent and/or treat CD1d+ cancers, such as T lymphoma. Cancer Immunol Res; 2(1); 59–69. ©2013 AACR.
Sex Difference in Risk of Second but Not of First Venous Thrombosis
Authors: Roach Rachel E.J. , Lijfering Willem M. , Rosendaal Frits R. , Cannegieter Suzanne C. , le Cessie Saskia 
Published: October 2013

Background—
The risk of recurrent venous thrombosis is 2-fold higher in men than in women. In contrast, no such sex difference in the risk of first venous thrombosis has been reported. We hypothesized that, for a first event, a risk difference between the sexes is masked by female exposure to reproductive factors (oral contraception, pregnancy/puerperium, and postmenopausal hormone therapy).

Methods and Results—
From the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study, a population-based case-control study on risk factors for venous thrombosis, 2915 patients with a first venous thrombosis and their partners as control subjects were included. Odds ratios and 95% confidence intervals for first venous thrombosis were assessed in men compared with women without reproductive risk factors by use of conditional logistic regression. Analyses were stratified in 10-year age categories to account for the variation in exposure to reproductive risk factors over different age groups and adjusted for body mass index and smoking. Overall, men had a 2.1-fold (95% confidence interval, 1.9–2.4) increased risk of first venous thrombosis compared with women without reproductive risk factors. Similar results were found when 10-year age categories were viewed separately. Adjustment for body mass index and smoking and exclusion of cancer patients did not materially affect the results.

Conclusions—
When female reproductive risk factors are taken into account, the risk of a first venous thrombosis is twice as high in men as in women. These findings are in line with previous studies on recurrent venous thrombosis and may have implications for future treatment and prevention strategies.
Activation of Histone Deacetylase-6 Induces Contractile Dysfunction Through Derailment of α-Tubulin Proteostasis in Experimental and Human Atrial Fibrillation
Authors: Zhang Deli , Wu Chia-Tung , Qi XiaoYan , Meijering Roelien A.M. , Hoogstra-Berends Femke , Tadevosyan Artavazd , Cubukcuoglu Deniz Gunseli , Durdu Serkan , Akar Ahmet Ruchan , Sibon Ody C.M. , Nattel Stanley , Henning Robert H. , Brundel Bianca J.J.M. 
Published: October 2013

Background—
Atrial fibrillation (AF) is characterized by structural remodeling, contractile dysfunction, and AF progression. Histone deacetylases (HDACs) influence acetylation of both histones and cytosolic proteins, thereby mediating epigenetic regulation and influencing cell proteostasis. Because the exact function of HDACs in AF is unknown, we investigated their role in experimental and clinical AF models.

Methods and Results—

Tachypacing of HL-1 atrial cardiomyocytes and
Drosophila
pupae hearts significantly impaired contractile function (amplitude of Ca
2+
transients and heart wall contractions). This dysfunction was prevented by inhibition of HDAC6 (tubacin) and sirtuins (nicotinamide). Tachypacing induced specific activation of HDAC6, resulting in α-tubulin deacetylation, depolymerization, and degradation by calpain. Tachypacing-induced contractile dysfunction was completely rescued by dominant-negative HDAC6 mutants with loss of deacetylase activity in the second catalytic domain, which bears α-tubulin deacetylase activity. Furthermore, in vivo treatment with the HDAC6 inhibitor tubastatin A protected atrial tachypaced dogs from electric remodeling (action potential duration shortening, L-type Ca
2+
current reduction, AF promotion) and cellular Ca
2+
-handling/contractile dysfunction (loss of Ca
2+
transient amplitude, sarcomere contractility). Finally, atrial tissue from patients with AF also showed a significant increase in HDAC6 activity and reduction in the expression of both acetylated and total α-tubulin.

Conclusions—
AF induces remodeling and loss of contractile function, at least in part through HDAC6 activation and subsequent derailment of α-tubulin proteostasis and disruption of the cardiomyocyte microtubule structure. In vivo inhibition of HDAC6 protects against AF-related atrial remodeling, disclosing the potential of HDAC6 as a therapeutic target in clinical AF.