bluuebunny/crossref_metadata_2025_split huggingface dataset:
Varicella-Zoster Virus Immediate-Early Protein ORF61 Abrogates the IRF3-Mediated Innate Immune Response through Degradation of Activated IRF3
Authors: Zhu Huifang , Zheng Chunfu , Xing Junji , Wang Shuai , Li Shuping , Lin Rongtuan , Mossman Karen L. 
Published: August 2011

ABSTRACT
Varicella-zoster virus (VZV) infection of differentiated cells within the host and establishment of latency likely requires evasion of innate immunity and limits secretion of antiviral cytokines. Here we report that its immediate-early protein ORF61 antagonizes the beta interferon (IFN-β) pathway. VZV infection down-modulated the Sendai virus (SeV)-activated IFN-β pathway, including mRNA of IFN-β and its downstream interferon-stimulated genes (ISGs), ISG54 and ISG56. Through a primary screening of VZV genes, we found that ORF61 inhibited SeV-mediated activation of IFN-β and ISRE (IFN-stimulated response element) promoter activities but only slightly affected NF-κB promoter activity, implying that the IFN-β pathway may be blocked in the IRF3 branch. An indirect immunofluorescence assay demonstrated that ectopic expression of ORF61 abrogated the detection of IRF3 in SeV-infected cells; however, it did not affect endogenous dormant IRF3 in noninfected cells. Additionally, ORF61 was shown to be partially colocalized with activated IRF3 in the nucleus upon treatment with MG132, an inhibitor of proteasomes, and the direct interaction between ORF61 and activated IRF3 was confirmed by a coimmunoprecipitation assay. Furthermore, Western blot analysis demonstrated that activated IRF3 was ubiquitinated in the presence of ORF61, suggesting that ORF61 degraded phosphorylated IRF3 via a ubiquitin-proteasome pathway. Semiquantitative reverse transcription-PCR (RT-PCR) analysis demonstrated that the level of ISG54 and ISG56 mRNAs was also downregulated by ORF61. Taken together, our results convincingly demonstrate that ORF61 down-modulates the IRF3-mediated IFN-β pathway by degradation of activated IRF3 via direct interaction, which may contribute to the pathogenesis of VZV infection.
Nonnucleoside Reverse Transcriptase Inhibitor-Resistant HIV Is Stimulated by Efavirenz during Early Stages of Infection
Authors: Wang Jiong , Zhang Gang , Bambara Robert A. , Li Dongge , Liang Hua , Wu Hulin , Smith Hannah M. , Lowe Nicholas R. , Demeter Lisa M. , Dykes Carrie 
Published: August 2011

ABSTRACT
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are potent and commonly prescribed antiviral agents used in combination therapy (CART) of human immunodeficiency virus type 1 (HIV-1) infection. The development of drug resistance is a major limitation of CART. Reverse transcriptase (RT) genotypes with the NNRTI resistance mutations K101E+G190S are highly resistant to efavirenz (EFV) and can develop during failure of EFV-containing regimens in patients. We have previously shown that virus with K101E+G190S mutations can replicate more efficiently in the presence of EFV than in its absence. In this study, we evaluated the underlying mechanism for drug-dependent stimulation, using a single-cycle cell culture assay in which EFV was added either during the infection or the virus production step. We determined that EFV stimulates K101E+G190S virus during early infection and does not affect late steps of virus replication, such as increasing the amount of active RT incorporated into virions. Additionally, we showed that another NNRTI, nevirapine (NVP), stimulated K101E+G190S virus replication during the early steps of infection similar to EFV, but that the newest NNRTI, etravirine (ETR), did not. We also showed that EFV stimulates K101E+Y188L and K101E+V106I virus, but not K101E+L100I, K101E+K103N, K101E+Y181C, or K101E+G190A virus, suggesting that the stimulation is mutation specific. Real-time PCR of reverse transcription intermediates showed that although the drug did not stimulate minus-strand transfer, it did stimulate minus-strand strong-stop DNA synthesis. Our results indicate that stimulation most likely occurs through a mechanism whereby NNRTIs stimulate priming or elongation of the tRNA.
Primary Infection by a Human Immunodeficiency Virus with Atypical Coreceptor Tropism
Authors: Jiang Chunlai , Parrish Nicholas F. , Wilen Craig B. , Li Hui , Chen Yue , Pavlicek Jeffrey W. , Berg Anna , Lu Xiaozhi , Song Hongshuo , Tilton John C. , Pfaff Jennifer M. , Henning Elizabeth A. , Decker Julie M. , Moody M. Anthony , Drinker Mark S. , Schutte Robert , Freel Stephanie , Tomaras Georgia D. , Nedellec Rebecca , Mosier Donald E. , Haynes Barton F. , Shaw George M. , Hahn Beatrice H. , Doms Robert W. , Gao Feng 
Published: August 2011

ABSTRACT

The great majority of human immunodeficiency virus type 1 (HIV-1) strains enter CD4
+
target cells by interacting with one of two coreceptors, CCR5 or CXCR4. Here we describe a transmitted/founder (T/F) virus (ZP6248) that was profoundly impaired in its ability to utilize CCR5 and CXCR4 coreceptors on multiple CD4
+
cell lines as well as primary human CD4
+
T cells and macrophages
in vitro
yet replicated to very high titers (>80 million RNA copies/ml) in an acutely infected individual. Interestingly, the envelope (Env) glycoprotein of this clade B virus had a rare GPEK sequence in the crown of its third variable loop (V3) rather than the consensus GPGR sequence. Extensive sequencing of sequential plasma samples showed that the GPEK sequence was present in virtually all Envs, including those from the earliest time points after infection. The molecularly cloned (single) T/F virus was able to replicate, albeit poorly, in cells obtained from
ccr5
Δ32
homozygous donors. The ZP6248 T/F virus could also infect cell lines overexpressing the alternative coreceptors GPR15, APJ, and FPRL-1. A single mutation in the V3 crown sequence (GPEK->GPGK) of ZP6248 restored its infectivity in CCR5
+
cells but reduced its ability to replicate in GPR15
+
cells, indicating that the V3 crown motif played an important role in usage of this alternative coreceptor. These results suggest that the ZP6248 T/F virus established an acute
in vivo
infection by using coreceptor(s) other than CCR5 or CXCR4 or that the CCR5 coreceptor existed in an unusual conformation in this individual.
Alternative Coreceptor Requirements for Efficient CCR5- and CXCR4-Mediated HIV-1 Entry into Macrophages
Authors: Cashin Kieran , Roche Michael , Sterjovski Jasminka , Ellett Anne , Gray Lachlan R. , Cunningham Anthony L. , Ramsland Paul A. , Churchill Melissa J. , Gorry Paul R. 
Published: August 2011

ABSTRACT

Macrophage tropism of human immunodeficiency virus type 1 (HIV-1) is distinct from coreceptor specificity of the viral envelope glycoproteins (Env), but the virus-cell interactions that contribute to efficient HIV-1 entry into macrophages, particularly via CXCR4, are not well understood. Here, we characterized a panel of HIV-1 Envs that use CCR5 (
n
= 14) or CXCR4 (
n
= 6) to enter monocyte-derived macrophages (MDM) with various degrees of efficiency. Our results show that efficient CCR5-mediated MDM entry by Env-pseudotyped reporter viruses is associated with increased tolerance of several mutations within the CCR5 N terminus. In contrast, efficient CXCR4-mediated MDM entry was associated with reduced tolerance of a large deletion within the CXCR4 N terminus. Env sequence analysis and structural modeling identified amino acid variants at positions 261 and 263 within the gp41-interactive region of gp120 and a variant at position 326 within the gp120 V3 loop that were associated with efficient CXCR4-mediated MDM entry. Mutagenesis studies showed that the gp41 interaction domain variants exert a significant but strain-specific influence on CXCR4-mediated MDM entry, suggesting that the structural integrity of the gp120-gp41 interface is important for efficient CXCR4-mediated MDM entry of certain HIV-1 strains. However, the presence of Ile326 in the gp120 V3 loop stem, which we show by molecular modeling is located at the gp120-coreceptor interface and predicted to interact with the CXCR4 N terminus, was found to be critical for efficient CXCR4-mediated MDM entry of divergent CXCR4-using Envs. Together, the results of our study provide novel insights into alternative mechanisms of Env-coreceptor engagement that are associated with efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages.
Parenchymal hematoma and total lesion volume in combined IV/IA revascularization stroke therapy
Authors: Tao Haiyang , Ramadas Gowri , Carrozzella Janice , Khatri Pooja , Broderick Joseph , Spilker Judith , Tomsick Thomas ,   for the IMS Investigators
Published: August 2011

Background and purposeA positive correlation between large parenchymal hematoma (PH) volume and large CT lesion volume in subjects treated with intravenous (IV) recombinant tissue plasminogen activator (rtPA) as well as placebo controls was identified in the European Cooperative Acute Stroke Study II (ECASS II). A study was undertaken to examine the relationship between PH volume and total lesion volume (including both cerebral infarction and hemorrhage) in subjects with symptomatic parenchymal hematoma (sPH) treated with combined IV and intra-arterial (IA) rtPA in the Interventional Management of Stroke (IMS) studies.MethodsHematoma and lesion volumes were measured planimetrically and by the ABC/2 method in 105 subjects from IMS studies I and II following combined IV and IA rtPA treatment. PH type 1 or 2 was determined by dichotomizing at >30% of lesion volume. Hematoma and lesion volumes for both symptomatic PH1 (sPH1) and PH2 (sPH2) types were compared using both measurement methods. Both sPH types were compared for baseline NIH Stroke Score, baseline Alberta Stroke Program Early CT score and treatment revascularization score based on the planimetric volume method.ResultsThe volume of sPH1 and sPH2 did not differ by either method of measurement. Subjects with sPH2 had a lower lesion volume compared with all PH1 (p=0.004) and sPH1 (p=0.02) by both methods. The ABC/2 method overestimated PH volume by 55±33% and lesion volume by 34±22% for sPH compared with the planimetric method.ConclusionsIn IMS I and II, hemorrhages in subjects with sPH2 were similar in volume to those in subjects with sPH1 and were associated with a smaller rather than a larger total lesion volume compared with other PH in the setting of combined IV/IA therapy. The use of PH2 as a sole surrogate for sPH in studies of stroke treatment may underestimate the incidence of clinically significant hemorrhage.
Prevalence of respiratory pathogens in diseased, non‐vaccinated, routinely medicated veal calves
Authors: Pardon B. , De Bleecker K. , Dewulf J. , Callens J. , Boyen F. , Catry B. , Deprez P. 
Published: August 2011

The prevalence of respiratory pathogens in diseased veal calves was determined in 24 respiratory disease outbreaks in 15 herds in Belgium. Bacteria were cultured from nasopharyngeal swabs and seroconversion against viruses and Mycoplasma bovis was determined on paired sera. At the individual calf level, Mycoplasma species, Mannheimia haemolytica and Pasteurella multocida, were isolated from 70.5 per cent, 21.5 per cent and 26.0 per cent of swabs, respectively. At the herd level, the presence of M bovis could be confirmed in 84.6 per cent of the herds examined. Seroconversion against bovine viral diarrhoea virus (BVDV) was present in 71.4 per cent of herds, parainfluenzavirus type 3 in 53.3 per cent, bovine respiratory syncytial virus in 40.0 per cent, bovine adenovirus type 3 in 46.7 per cent, bovine coronavirus in 30.0 per cent, and bovine herpesvirus type 1 in 26.7 per cent. At postmortem examination, Mycoplasma species could be cultured from 61.9 per cent of pneumonic lungs (n=21). Sixty per cent of calves tested were positive for BVDV (n=20), and 20.0 per cent were positive for bovine respiratory syncytial virus (n=16).
Synergistic Action of a RAF Inhibitor and a Dual PI3K/mTOR Inhibitor in Thyroid Cancer
Authors: Jin Ning , Jiang Tianyun , Rosen David M. , Nelkin Barry D. , Ball Douglas W. 
Published: August 2011

Abstract
Purpose: In thyroid cancer clinical trials, agents targeting VEGF receptors (VEGFR) and RET, among other kinases, have led to partial responses but few complete or durable responses. The RAF–MEK–ERK and PI3K–AKT–mTOR signaling pathways are frequently activated in differentiated and medullary thyroid cancer (DTC and MTC) and may provide therapeutic targets for these diseases. We tested a novel drug combination targeting RAF, phosphoinositide 3-kinase (PI3K), and mTOR, plus VEGFR2 and RET, in thyroid cancer preclinical models with defined genetic backgrounds.
Experimental Design: RAF265, an ATP-competitive pan-RAF inhibitor active against VEGFR2, and BEZ-235, a PI3K inhibitor also active against Torc1 and Torc2, were tested alone and in combination in a panel of thyroid cancer lines. We tested RAF265 and BEZ-235 for kinase inhibition, growth inhibition and cell-cycle alterations, and inhibition of signaling targets and tumor growth in xenograft models.
Results: Both drugs potently inhibited their kinase targets in the extracellular signal-regulated kinase (ERK) and PI3K pathways. In addition, RAF265 had significant RET inhibitory activity (IC50 = 25–50 nmol/L for RETC634W). The combination strongly inhibited proliferation of DTC and MTC cell lines with mutations in RAS, BRAF, PTEN, and RET. Synergy was shown for B-CPAP (BRAFV600E) and TT cells (RETC634W). The combination of both drugs significantly inhibited growth of CAL62 (KRASG12R/G12R) and TT xenografts, thoroughly inhibiting ERK and PI3K pathway signaling.
Conclusions: Combined blockade of ERK and PI3K signaling potently inhibits growth in preclinical models representing the key genotypes seen in refractory thyroid cancer. These targets and therapies are promising for further development in both differentiated and medullary thyroid cancers. Clin Cancer Res; 17(20); 6482–9. ©2011 AACR.
Maintained Sensitivity to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Lung Cancer Recurring after Adjuvant Erlotinib or Gefitinib
Authors: Oxnard Geoffrey R. , Janjigian Yelena Y. , Arcila Maria E. , Sima Camelia S. , Kass Samantha L. , Riely Gregory J. , Pao William , Kris Mark G. , Ladanyi Marc , Azzoli Christopher G. , Miller Vincent A. 
Published: August 2011

Abstract
Purpose: Given the unprecedented efficacy of EGFR tyrosine kinase inhibitors (TKI) in advanced EGFR-mutant lung cancer, adjuvant TKI therapy is an appealing strategy. However, there are conflicting findings regarding the potential benefit of adjuvant EGFR-TKI in patients with lung cancer harboring EGFR mutations. To better understand these results, we studied the natural history of lung cancers which recurred despite adjuvant TKI.
Experimental Design: Patients with recurrent EGFR-mutant lung cancer following adjuvant TKI were identified using an Institutional Review Board-approved mechanism. Recurrent cancer specimens were tested for resistance mutations. Sensitivity to retreatment with EGFR-TKI was evaluated.
Results: Twenty-two patients with cancers harboring an EGFR sensitizing mutation received adjuvant erlotinib or gefitinib for a median of 17 months (range 1–37 months). T790M was more common in cancers which recurred while receiving TKI than in those which recurred after stopping TKI (67% vs. 0%, P = 0.011). Fourteen patients who developed recurrence after stopping EGFR-TKI were retreated, with a median time to progression of 10 months and radiographic response seen in 8 of 11 patients with evaluable disease (73%).
Conclusions: Recurrence of EGFR-mutant lung cancer after stopping adjuvant TKI should not preclude a trial of TKI retreatment; a phase II trial of erlotinib in this setting is underway. Studies of adjuvant EGFR-TKI will underestimate the potential survival benefit of adjuvant TKI for patients with EGFR-mutant lung cancers if retreatment at recurrence is not given. Clin Cancer Res; 17(19); 6322–8. ©2011 AACR.
A Phase I First-in-Human Pharmacokinetic and Pharmacodynamic Study of Serdemetan in Patients with Advanced Solid Tumors
Authors: Tabernero Josep , Dirix Luc , Schöffski Patrick , Cervantes Andrés , Lopez-Martin Jose Antonio , Capdevila Jaume , van Beijsterveldt Ludy , Platero Suso , Hall Brett , Yuan Zhilong , Knoblauch Roland , Zhuang Sen Hong 
Published: August 2011

Abstract
Purpose: Originally isolated on the basis of its ability to induce p53, serdemetan showed potent activity in various preclinical models, inducing S-phase arrest and apoptosis in TP53 wild-type and mutant tumors. This study evaluated the safety and tolerability of serdemetan, determined the pharmacokinetic and pharmacodynamic profiles, and identified a recommended phase II dose.
Patients and Methods: Patients (71) with refractory solid tumors were allocated to dose-escalating cohorts (3+3 patients each) and received oral serdemetan once daily in 21-day cycles to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Plasma was collected for pharmacokinetic analyses. Paired baseline and on-treatment skin and tumor biopsies were done; blood samples were collected for pharmacodynamic analyses, including p53 and macrophage inhibitory cytokine-1 induction.
Results: The MTD of serdemetan was determined to be 350 mg once daily. During this study, grade 3 QTc prolongation was the most common DLT and nausea (66.2%) was the most frequent treatment-emergent adverse event. Serdemetan was rapidly absorbed after oral administration and exhibited dose-proportional pharmacokinetics. At steady state, mean maximum plasma concentration (Cmax) was 2,330 ng/mL and mean area under plasma concentration curve (AUC0–24h) was 43.0 μg.h/mL, with serdemetan 300 mg/d. There was a dose- and exposure-dependent p53 induction. One patient with breast cancer showed a partial response; 22 (38.6%) patients had stable disease.
Conclusions: Serdemetan treatment was associated with p53 induction in both tumor and surrogate tissue pharmacodynamic studies and modest clinical activity. Although serdemetan was well tolerated with dose-proportional pharmacokinetics, exposure-related QTc liability was observed. Clin Cancer Res; 17(19); 6313–21. ©2011 AACR.
CYP2S1 and CYP2W1 Mediate 2-(3,4-Dimethoxyphenyl)-5-Fluorobenzothiazole (GW-610, NSC 721648) Sensitivity in Breast and Colorectal Cancer Cells
Authors: Tan Boon Shing , Tiong Kai Hung , Muruhadas Ashwin , Randhawa Nirmal , Choo Heng Lungh , Bradshaw Tracey D. , Stevens Malcolm F.G. , Leong Chee-Onn 
Published: August 2011

AbstractBoth 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F-203; NSC 703786) and 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (GW-610; NSC 721648) are antitumor agents with novel mechanism(s). Previous studies have indicated that cytochrome (CYP) P450 1A1 is crucial for 5F-203 activity. In the present study, we investigated the functional role of 2 newly identified CYP P450 enzymes, CYP2S1 and CYP2W1, in mediating antitumor activity of benzothiazole compounds. We generated isogenic breast cancer (MDA-MB-468, MCF-7) and colorectal cancer (CRC; KM12 and HCC2998) cell lines depleted for CYP1A1, CYP2S1, or CYP2W1. The sensitivity of these cells to 5F-203 and GW-610 was then compared with vector control cells. 5F-203 exhibited potent activity against breast cancer cells, whereas GW-610 was effective against both breast and colorectal cancer cells. CYP1A1 was induced in both breast cancer and CRC cells, while CYP2S1 and CYP2W1 were selectively induced in breast cancer cells only following treatment with 5F-203 or GW-610. Depletion of CYP1A1 abrogated the sensitivity of breast cancer and CRC cells to 5F-203 and GW-610. Although depletion of CYP2S1 sensitized both breast cancer and CRC cells toward 5F-203 and GW-610, CYP2W1 knockdown caused marked resistance to GW-610 in CRC cells. Our results indicate that CYP-P450 isoforms, with the exception of CYP1A1, play an important role in mediating benzothiazole activity. CYP2S1 appears to be involved in deactivation of benzothiazoles, whereas CYP2W1 is important for bioactivation of GW-610 in CRC cells. Because CYP2W1 is highly expressed in colorectal tumors, GW-610 represents a promising agent for CRC therapy. Mol Cancer Ther; 10(10); 1982–92. ©2011 AACR.
In families with inherited thrombophilia the risk of venous thromboembolism is dependent on the clinical phenotype of the proband
Authors: Rossi Elena , Ciminello Angela , Za Tommaso , Betti Silvia , Leone Giuseppe , Stefano Valerio 
Published: August 2011

SummaryThe utility of laboratory investigation of relatives of individuals with inherited thrombophilia is uncertain. To assess the risk of venous thromboembolism (VTE) among the carriers, we investigated a family cohort of 1,720 relatives of probands with thrombophilia who were evaluated because of VTE (n=1,088), premature arterial thrombosis (n=113), obstetric complication (n=257), or universal screening before pregnancy or hormonal contraception or therapy (n=262); 968 relatives were carriers of thrombophilia. A first deep venous thrombosis (DVT) occurred in 44 carriers and 10 non-carriers during 37,688 and 29,548 observationyears from birth, respectively. The risk of DVT among the carriers compared with non-carriers was estimated as a hazard ratio (HR). If the proband had VTE and factor V Leiden (FVL) and/or prothrombin (PT)20210A, the HR for DVT was 2.77 (95%CI 1.21–4.82) in the carriers overall, and 5.54 (95%CI 3.20–187.00) in those homozygous or double heterozygous for FVL and PT20210A. If the proband had VTE and a deficiency of antithrombin (AT), protein C or S, the HR for DVT was 5.14 (95%CI 0.88–10.03) in the carriers overall, and 12.86 (95%CI 2.46–59.90) in those with AT deficiency. No increase in risk was found among the carriers who were relatives of the probands who were evaluated for reasons other than VTE. In conclusion, familial investigation for inherited thrombophilia seems justified for probands with previous VTE, but appears of doubtful utility for the relatives of probands without VTE. This should be taken with caution regarding families with deficiency of natural anticoagulants, given the low number of cases analysed.
Disease burden and unmet needs for prevention of venous thromboembolism in medically ill patients in Europe show underutilisation of preventive therapies
Authors: Welner Sharon , Kubin Maria , Folkerts Kerstin , Haas Sylvia , Khoury Hanane 
Published: August 2011

SummaryIt was the aim of this review to assess the incidence of venous thromboembolism (VTE) and current practice patterns for VTE prophylaxis among medical patients with acute illness in Europe. A literature search was conducted on the epidemiology and prophylaxis practices of VTE prevention among adult patients treated in-hospital for major medical conditions. A total of 21 studies with European information published between 1999 and April 2010 were retrieved. Among patients hospitalised for an acute medical illness, the incidence of VTE varied between 3.65% (symptomatic only over 10.9 days) and 14.9% (asymptomatic and symptomatic over 14 days). While clinical guidelines recommend pharmacologic VTE prophylaxis for patients admitted to hospital with an acute medical illness who are bedridden, clear identification of specific risk groups who would benefit from VTE prophylaxis is lacking. In the majority of studies retrieved, prophylaxis was under-used among medical inpatients; 21% to 62% of all patients admitted to the hospital for acute medical illnesses did not receive VTE prophylaxis. Furthermore, among patients who did receive prophylaxis, a considerable proportion received medication that was not in accord with guidelines due to short duration, suboptimal dose, or inappropriate type of prophylaxis. In most cases, the duration of VTE prophylaxis did not exceed hospital stay, the mean duration of which varied between 5 and 11 days. In conclusion, despite demonstrated efficacy and established guidelines supporting VTE prophylaxis, utilisation rates and treatment duration remain suboptimal, leaving medical patients at continued risk for VTE. Improved guideline adherence and effective care delivery among the medically ill are stressed.