bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis, Structure, and Behavior in Solution of the Dawson Thio Derivative [(P2W17O61)2(H4Mo4S4O6)]16–
Authors: Pilette Marie‐Anne , Floquet Sébastien , Marrot Jérôme , Cadot Emmanuel
Published: July 2011

The [(P4W34O61)2{Mo4S4O4(OH2)2}]16– anion was obtained by the stereospecific addition of the [Mo2S2O2]2+ oxothio cation to the monovacant α2‐[P2W17O61]10– anion. The mixed salt K9Na7[(P2W17O61)2{Mo4S4O4(OH2)2}]·50H2O was isolated as single crystals and characterized by X‐ray diffraction. The analysis reveals that the anion adopts a “sandwich‐like” dimeric structure in which the two α2‐[P2W17O61]10– subunits are assembled in a transoid disposition with respect to the central cluster {H4Mo4S4O6}. In aqueous solution, an isomerization process is evidenced by 31P NMR spectroscopy and interpreted as the formation of the related cisoid isomer. A ratio of 30:70 of the transoid and cisoid isomers was found at equilibrium. The kinetic constants and activation parameters of the isomerization process were determined by variable‐temperature 31P NMR experiments. At 303 K, the process was slow (t1/2 = 160 min). The activation parameters are discussed with regard to a possible isomerization mechanism.
Sulfoximines as a Versatile Scaffold for Electrophilic Fluoroalkylating Reagents
Authors: Urban Céline , Cadoret Frédéric , Blazejewski Jean‐Claude , Magnier Emmanuel
Published: July 2011

New electrophilic fluoroalkylating agents based on the sulfoximine skeleton as a common platform are described. We demonstrate the importance of the activating group, attached to the nitrogen, and its specificity for the fluorinated group to be delivered. As an application, a variety of unknown dichlorofluoro, bromodifluoro, and trifluoromethyl alkynes have been prepared using these reagents.
Oil dispersant preparation and mechanisms for waste oil‐based drilling fluids
Authors: Guancheng Jiang , Shuixiang Xie , Mian Chen , Zhiyong Li , Hao Deng , Hui Mao , Weihang Zhang , Jihui Ding
Published: July 2011

Waste oil‐based drilling fluids (WOBDF) contain oil, heavy metals, organic matter, and other pollutants and are classified as hazardous wastes in China and other countries. WOBDF produce harmful effects on the ecological environment and are often difficult to treat. At present, WOBDF are generally subject to landfills or re‐injection in formulations, which not only waste valuable land resources but also produce severe environmental pollution. On the basis of numerous laboratory and field studies, oil dispersant ELO‐1 was developed to recover oil from WOBDF. The components of oil dispersant ELO‐1 are the following: 30% composite demulsifier FPR‐1, 1.5% coagulant CC, and 2% flocculant PAM (0.1%). The corresponding temperature range is 40–60°C. This article combines the use of oil dispersant ELO‐1 with centrifugal separation to recover oil from Daqing Oilfield WOBDF. The average recovery rate was 89.7% with water and sand content <0.1%. The residual mud slag was treated to control its hazardous components and was then used as a material for cofferdam building and road paving. Therefore, the harmless treatment and utilization of WOBDF objectives were achieved. © 2011 American Institute of Chemical Engineers Environ Prog, 2011
On the performance of lumped parameter models with gyro‐mass elements for the impedance function of a pile‐group supporting a single‐degree‐of‐freedom system
Authors: Saitoh Masato
Published: July 2011

Lumped parameter models with a so called “gyro‐mass” element (GLPMs) have been proposed recently in response to a strong demand for efficiently and accurately representing frequency‐dependent impedance functions of soil–foundation systems. Although GLPMs are considered to be powerful tools for practical applications in earthquake engineering, some problems remain. For instance, although GLPMs show fairly close agreement with the target impedance functions, the accuracy of the transfer functions and the time‐histories of dynamic responses in structural systems comprising GLPMs have never been verified. Furthermore, no assessment has been performed on how much difference appears in the accuracy of dynamic responses obtained from GLPMs and those from conventional Kelvin–Voigt models comprising a spring and a dashpot arranged in parallel with various frequency‐independent constants. Therefore, in this paper, these problems are examined using an example of 2×4 pile groups embedded in a layered soil medium, supporting a single‐degree‐of‐freedom system subjected to ground motions. The results suggest that GLPMs are a new option for highly accurate computations in evaluating the dynamic response of structural systems comprising typical pile groups, rather than conventional Kelvin–Voigt models. Copyright © 2011 John Wiley & Sons, Ltd.
The use of integrated sedimentological and geophysical methods in drumlin research – a case study of Pigeon Point, Clew Bay, Northwest Ireland
Authors: Hiemstra John F. , Kulessa Bernd , King Edward C. , Ntarlagiannis Dimitris
Published: July 2011

Despite significant advances over the past decades, our understanding of drumlin formation and associated ice‐bed processes is still incomplete. In this paper, we present the integrated use of geomorphological, sedimentological and geophysical techniques as a powerful means to force a breakthrough towards solving the drumlin enigma.

We report on investigations of the anatomy of the Pigeon Point drumlin, Clew Bay, Ireland. We found that the bulk of the landform, which displays a classical drumlin shape, consists of silty‐clayey diamicton showing evidence of deformation, hydrofracturing and comminution. The unit is interpreted as a sub‐glacial traction till/comminution till. The thin unit overlying this basal till consists of silty‐sandy diamicton, and is interpreted as a para‐glacially modified melt‐out till. The partly cemented third unit consists of stratified, massive to graded sands and gravels. Its contact with the sub‐glacial traction till consists of a series of concave shapes, which suggests that it was deposited in meltwater channels that flowed in sub‐glacial cavities and that cut laterally into the drumlin.

We propose that highs in the undulating rockhead relief, as shown in the seismic profile, have provided nuclei which initiated drumlin formation. This idea is supported by the observation of local detached bedrock slabs that grade upwards into a comminution till. In the long profile, very high normalized induced polarization (IP) values form a wedge‐shape, which is interpreted as a set of conjugate thrusts, or a ‘pop‐up’ structure. The structure is positioned directly above one of the undulations in the bedrock, suggesting a direct relationship. The high values are thought to reflect the presence of pre‐existing clays, which were sheared into the till, thus forming linings in the thrust features. It is concluded that glacitectonic processes, notably differential bedrock weathering and thrusting, have played a key role in the formation of this drumlin. Copyright © 2011 John Wiley & Sons, Ltd.
Computer simulation of third‐order nonlinear singular problems arising in draining and coating flows
Authors: Kumar Manoj , Singh Neelima
Published: July 2011

In this paper, the nonlinear third‐order singular ordinary differential equations that arise in draining and coating flows are studied and computationally solved by employing the modified Adomian decomposition method, and the series solutions of the governing nonlinear problems are developed. Because of singularity, it is not possible to move a contact line over a no‐slip surface, so we cannot find the solution of such problems. To overcome this difficulty, we modify boundary condition to apply the modified Adomian decomposition method with Padé approximants. Copyright © 2011 John Wiley & Sons, Ltd.
Twisting the Dollar? On the Consistency of Short‐Run and Long‐Run Exchange Rate Expectations
Authors: Frenkel Michael , Rülke Jan‐Christoph , Stadtmann Georg
Published: July 2011

We examine consistency properties of the exchange rate expectation formation process of short‐run and long‐run forecasts in the dollar/euro and yen/dollar market. Applying nonlinear consistency restrictions we show that in a simple expectation formation structure short‐run forecasts are indeed inconsistent with long‐run predictions. Moreover, we establish a ‘twist’ in the dollar/euro expectation formation process, i.e. market participants expect bandwagon effects in the short run, while they have stabilizing expectations in their long‐run forecasts. Applying a panel probit analysis we find that this twisting behavior is more likely to occur in periods of excess exchange rate volatility. Copyright © 2011 John Wiley & Sons, Ltd.
The clinical impact and molecular biology of del(17p) in multiple myeloma treated with conventional or thalidomide‐based therapy
Authors: Boyd Kevin D. , Ross Fiona M. , Tapper William J. , Chiecchio Laura , Dagrada GianPaolo , Konn Zoe J. , Gonzalez David , Walker Brian A. , Hockley Sarah L. , Wardell Christopher P. , Gregory Walter M. , Anthony Child J. , Jackson Graham H. , Davies Faith E. , Morgan Gareth J. ,   on behalf of the NCRI Haematology Oncology Studies Group
Published: July 2011

Hemizygous deletion of 17p (del(17p)) has been identified as a variable associated with poor prognosis in myeloma, although its impact in the context of thalidomide therapy is not well described. The clinical outcome of 85 myeloma patients with del(17p) treated in a clinical trial incorporating both conventional and thalidomide‐based induction therapies was examined. The clinical impact of deletion, low expression, and mutation of TP53 was also determined. Patients with del(17p) did not have inferior response rates compared to patients without del(17p), but, despite this, del(17p) was associated with impaired overall survival (OS) (median OS 26.6 vs. 48.5 months, P < 0.001). Within the del(17p) group, thalidomide induction therapy was associated with improved response rates compared to conventional therapy, but there was no impact on OS. Thalidomide maintenance was associated with impaired OS, although our analysis suggests that this effect may have been due to confounding variables. A minimally deleted region on 17p13.1 involving 17 genes was identified, of which only TP53 and SAT2 were underexpressed. TP53 was mutated in <1% in patients without del(17p) and in 27% of patients with del(17p). The higher TP53 mutation rate in samples with del(17p) suggests a role for TP53 in these clinical outcomes. In conclusion, del(17p) defined a patient group associated with short survival in myeloma, and although thalidomide induction therapy was associated with improved response rates, it did not impact OS, suggesting that alternative therapeutic strategies are required for this group. © 2011 Wiley‐Liss, Inc.
Somatic mutations of the mitochondrial genome in human breast cancers
Authors: Tseng Ling‐Ming , Yin Pen‐Hui , Yang Chu‐Wen , Tsai Yi‐Fang , Hsu Chih‐Yi , Chi Chin‐Wen , Lee Hsin‐Chen
Published: July 2011

Somatic mutations in mitochondrial DNA (mtDNA) have been identified in various tumors, including breast cancer. However, their clinicopathological impact on breast cancer still remains unclear. In this study, we re‐sequenced the entire mtDNA from breast cancer samples together with paired non‐tumorous breast tissues from 58 Taiwanese patients. We identified 19 somatic mutations in the mtDNA coding region of 16 breast cancers. Out of these mutations, 12 of the 19 mutations (63%) are missense or frame‐shift mutations that have the potential to cause mitochondrial dysfunction. In combination with our previously study on the D‐loop region of mtDNA, we found that 47% (27/58) of the breast cancers harbored somatic mtDNA mutations. Among a total of 40 somatic mutations, 53% (21/40) were located in the D‐loop region of the mtDNA, 5% (2/40) were in the ribosomal RNA genes, 5% (2/40) were in the tRNA genes, and 38% (15/40) occurred in mRNA genes. The occurrence of these somatic mtDNA mutations is associated with an older onset age (≥50‐year old, P = 0.039), a higher TNM stage (P = 0.027), and a higher histological grade (P = 0.012). Multiple logistic regression analysis revealed that an older onset age (P = 0.029) and a higher histological grade (P = 0.006) are significantly correlated with patients having somatic mutations in the mtDNA in their breast cancer sample. In conclusion, our results suggest that somatic mtDNA mutations may play a critical role in the progression of breast cancer. © 2011 Wiley‐Liss, Inc.
Tissue transglutaminase activity is involved in the differentiation of oligodendrocyte precursor cells into myelin‐forming oligodendrocytes during CNS remyelination
Authors: Van Strien Miriam E. , Baron Wia , Bakker Erik N.T.P. , Bauer Jan , Bol John G.J.M. , Brevé John J.P. , Binnekade Rob , Van Der Laarse Willem J. , Drukarch Benjamin , Van Dam Anne‐Marie
Published: July 2011

During normal brain development, axons are myelinated by mature oligodendrocytes (OLGs). Under pathological, demyelinating conditions within the central nervous system (CNS), axonal remyelination is only partially successful because oligodendrocyte precursor cells (OPCs) largely remain in an undifferentiated state resulting in a failure to generate myelinating OLGs. Tissue Transglutaminase (TG2) is a multifunctional enzyme, which amongst other functions, is involved in cell differentiation. Therefore, we hypothesized that TG2 contributes to differentiation of OPCs into OLGs and thereby stimulates remyelination. In vivo studies, using the cuprizone model for de‐ and remyelination in TG2−/− and wild‐type mice, showed that during remyelination expression of proteolipid protein mRNA, as a marker for remyelination, in the corpus callosum lags behind in TG2−/− mice resulting in less myelin formation and, moreover, impaired recovery of motor behavior. Subsequent in vitro studies showed that rat OPCs express TG2 protein and activity which reduces when the cells have matured into OLGs. Furthermore, when TG2 activity is pharmacologically inhibited, the differentiation of OPCs into myelin‐forming OLGs is dramatically reduced. We conclude that TG2 plays a prominent role in remyelination of the CNS, probably through stimulating OPC differentiation into myelin‐forming OLGs. Therefore, manipulating TG2 activity may represent an interesting new target for remyelination in demyelinating diseases. © 2011 Wiley‐Liss, Inc.
Comparison of bulbar and mucosal olfactory ensheathing cells using FACS and simultaneous antigenic bivariate cell cycle analysis
Authors: Kueh Jacqueline Li‐Ling , Raisman Geoffrey , Li Ying , Stevens Robert , Li Daqing
Published: July 2011

Transplantation of olfactory ensheathing cells (OECs) is a promising route for CNS repair. There have, however, been major discrepancies between the results from different groups. Part of this can be attributed to variations in cell sources and culture protocols. Accurate estimation of the proportions of OECs and their associated fibroblasts (ONFs) and their evolution with time in culture is an essential baseline for establishing the reparative properties of transplants. In this study, we compare the evolution of cultures from the superficial layers of the olfactory bulb with tissue from the olfactory mucosa, both whole and split into lamina propria and epithelial layer. We used FACS based on p75 and Thy1 to provide a robust and objective numerical estimate of the numbers of OECs and ONFs, respectively in the cultures. A novel four color simultaneous antigenic bivariate cell cycle analysis shows that proliferation of OECs is time‐limited, and is unable to prevent an overall loss of OECs with time. Overall, the numbers of OECs in the cultures were inversely correlated with the deposition of fibronectin (FN). Further, culture of the cells purified by flow cytometry shows that, whereas the Thy1 population is terminally differentiated, the p75 population from the mucosal samples generates subpopulations with different antigenic phenotypes, including the reappearance of a subpopulation of p75 cells expressing FN. Culturing epithelial samples at high density reveals an unexpected transient stem cell‐like population of rapidly proliferating p75 positive cells. © 2011 Wiley‐Liss, Inc.
The ribotoxin deoxynivalenol affects the viability and functions of glial cells
Authors: Razafimanjato Helisoa , Benzaria Amal , Taïeb Nadira , Guo Xiao‐Jun , Vidal Nicolas , Di Scala Coralie , Varini Karine , Maresca Marc
Published: July 2011

Glial cells are responsible for maintaining brain homeostasis. Modification of the viability and functions of glial cells, including astrocytes and microglia, are associated with neuronal death and neurological diseases. Many toxins (heavy metals, pesticides, bacterial or viral toxins) are known to impact on brain cell viability and functions. Although recent publications suggest a potential link between environmental exposure of humans to mycotoxins and neurological diseases, data regarding the effects of fungal toxins on brain cells are scarce. In the present study, we looked at the impact of deoxynivalenol (DON), a fungal ribotoxin, on glial cells from animal and human origin. We found that DON decreased the viability of glial cells with a higher toxicity against microglial cells compared with astrocytes. In addition to cellular toxicity, DON affected key functions of glial cells. Thus, DON caused a biphasic effect on the neuroinflammatory response of microglia to lipopolysaccharide (LPS), while sublethal doses of DON increased the LPS‐induced secretion of TNF‐α and nitric oxide, toxic doses inhibited it. In addition to affecting microglial functions, sublethal doses of DON also suppressed the uptake of L‐glutamate by astrocytes. This inhibition was associated with a modification of the expression of the glutamate transporters at the plasma membrane. Our results suggest that environmental ribotoxins such as DON could, at low doses, cause modifications of brain homeostasis and possibly participate in the etiology of neurological diseases in which alterations of the glia are involved. © 2011 Wiley‐Liss, Inc.
Salivary protein and solCD44 levels as a potential screening tool for early detection of head and neck squamous cell carcinoma
Authors: Franzmann Elizabeth J. , Reategui Erika P. , Pereira Lutecia H. Mateus , Pedroso Felipe , Joseph Debbie , Allen Glenn O. , Hamilton Kara , Reis Isildinha , Duncan Robert , Goodwin W. Jarrard , Hu Jennifer J. , Lokeshwar Vinata B.
Published: July 2011

Background

Head and neck squamous cell carcinoma (HNSCC) is a devastating disease usually diagnosed at a late stage when cure rates are 40%. We examined a simple and inexpensive molecular tool that may aid HNSCC detection.

Methods

Building on prior findings that total protein levels are elevated in 102 HNSCC cases versus 84 control subjects, we further analyzed these levels with respect to important risk and demographic variables and compared the results to soluble CD44 (solCD44). Using multivariate adaptive regression splines (MARSs)‐logit modeling and logistic regression, we determined whether total protein, solCD44, or the combination best identifies HNSCC.

Results

Combined higher levels of solCD44 and protein were significantly associated with HNSCC (odds ratio [OR] = 24.90; 95% confidence interval [CI], 9.04–68.57; area under the curve [AUC] = 0.786). A model including protein plus solCD44 resulted in a better area (AUC 0.796) than either marker alone.

Conclusion

Oral rinse levels of solCD44 and protein seem to hold promise for detection of HNSCC. © 2011 Wiley Periodicals, Inc. Head Neck, 2012
Oxidative stress pathways in noncancerous human liver tissue to predict hepatocellular carcinoma recurrence: A prospective, multicenter study
Authors: Tanaka Shinji , Mogushi Kaoru , Yasen Mahmut , Ban Daisuke , Noguchi Norio , Irie Takumi , Kudo Atsushi , Nakamura Noriaki , Tanaka Hiroshi , Yamamoto Masakazu , Kokudo Norihiro , Takayama Tadatoshi , Kawasaki Seiji , Sakamoto Michiie , Arii Shigeki
Published: July 2011

The prediction of cancer recurrence holds the key to improvement of the postoperative prognosis of patients. In this study, the recurrence of early-stage hepatocellular carcinoma (HCC) after curative hepatectomy was analyzed by the genome-wide gene-expression profiling on cancer tissue and the noncancerous liver tissue. Using the training set of 78 cases, the cytochrome P450 1A2 (CYP1A2) gene in noncancerous liver tissue was identified as the predictive candidate for postoperative recurrence (hazard ratio [HR], 0.447; 95% confidence interval [CI], 0.249-0.808;

P

= 0.010). Multivariate analysis revealed the statistically significant advantage of CYP1A2 down-regulation to predict recurrence (odds ratio, 0.534; 95% CI, 0.276-0.916;

P

= 0.036), and the expression of CYP1A2 protein was confirmed immunohistochemically. An independently multi-institutional cohort of 211 patients, using tissue microarrays, validated that loss of expression of CYP1A2 in noncancerous liver tissue as the only predictive factor of recurrence after curative hepatectomy for early-stage HCC (HR, 0.480; 95% CI, 0.256-0.902;

P

= 0.038). Gene set-enrichment analysis revealed close association of CYP1A2 down-regulation with oxidative stress pathways in liver tissue (

P

< 0.001, false discovery rate [FDR] = 0.042;

P

= 0.006, FDR = 0.035). Our results indicate these pathways as the molecular targets to prevent recurrence, as well as the potential prediction of the super high-risk population of HCC using liver tissue. (Hepatology 2011;54:1273–1281)
Circulating microRNAs as potential markers of human drug-induced liver injury
Authors: Starkey Lewis Philip J. , Dear James , Platt Vivien , Simpson Kenneth J. , Craig Darren G.N. , Antoine Daniel J. , French Neil S. , Dhaun Neeraj , Webb David J. , Costello Eithne M. , Neoptolemos John P. , Moggs Jonathan , Goldring Chris E. , Park Kevin B.
Published: July 2011

New biomarkers of liver injury are required in the clinic and in preclinical pharmaceutical evaluation. Previous studies demonstrate that two liver-enriched microRNAs (miR-122 and miR-192) are promising biomarkers of acetaminophen-induced acute liver injury (APAP-ALI) in mice. We have examined these molecules, for the first time, in humans with APAP poisoning. Serum miR-122 and miR-192 were substantially higher in APAP-ALI patients, compared to healthy controls (median ΔΔCt [25th, 75th percentile]) (miR-122: 1,265 [491, 4,270] versus 12.1 [7.0, 26.9], P < 0.0001; miR-192: 6.9 [2.0, 29.2] versus 0.44 [0.30, 0.69], P < 0.0001). A heart-enriched miR-1 showed no difference between APAP-ALI patients and controls, whereas miR-218 (brain-enriched) was slightly higher in the APAP-ALI cohort (0.17 [0.07, 0.50] versus 0.07 [0.04, 0.12]; P = 0.01). In chronic kidney disease (CKD) patients, miR-122 and -192 were modestly higher, compared to controls (miR-122: 32.0 [21.1, 40.9] versus 12.1 [7.0, 26.9], P = 0.006; miR-192: 1.2 [0.74, 1.9] versus 0.44 [0.30, 0.69], P = 0.005), but miR-122 and -192 were substantially higher in APAP-ALI patients than CKD patients (miR-122: P < 0.0001; miR-192: P < 0.0004). miR-122 correlated with peak ALT levels in the APAP-ALI cohort (Pearson R = 0.46, P = 0.0005), but not with prothrombin time. miR-122 was also raised alongside peak ALT levels in a group of patients with non-APAP ALI. Day 1 serum miR-122 levels were almost 2-fold higher in APAP-ALI patients who satisfied King's College Criteria (KCC), compared to those who did not satisfy KCC, although this did not reach statistical significance (P = 0.15). Conclusion: This work provides the first evidence for the potential use of miRNAs as biomarkers of human drug-induced liver injury. (Hepatology 2011;)
Role of cyclophilin B in tumorigenesis and cisplatin resistance in hepatocellular carcinoma in humans
Authors: Kim Yeonghwan , Jang Miran , Lim Sangbin , Won Hyeran , Yoon Kyung-Sik , Park Jae-Hoon , Kim Hyo Jong , Kim Byung-Ho , Park Won-Sang , Ha Joohun , Kim Sung-Soo
Published: July 2011

Cyclophilin B (CypB) performs diverse roles in living cells, but its role in hepatocellular carcinoma (HCC) is largely unclear. To reveal its role in HCC, we investigated the induction of CypB under hypoxia and its functions in tumor cells in vitro and in vivo. Here, we demonstrated that hypoxia-inducible factor 1α (HIF-1α) induces CypB under hypoxia. Interestingly, CypB protected tumor cells, even p53-defective HCC cells, against hypoxia- and cisplatin-induced apoptosis. Furthermore, it regulated the effects of HIF-1α, including those in angiogenesis and glucose metabolism, via a positive feedback loop with HIF-1α. The tumorigenic and chemoresistant effects of CypB were confirmed in vivo using a xenograft model. Finally, we showed that CypB is overexpressed in 78% and 91% of the human HCC and colon cancer tissues, respectively, and its overexpression in these cancers reduced patient survival. Conclusions: These results indicate that CypB induced by hypoxia stimulates the survival of HCC via a positive feedback loop with HIF-1α, indicating that CypB is a novel candidate target for developing chemotherapeutic agents against HCC and colon cancer. (Hepatology 2011;).
Hepatotoxicity mediated by pyrazole (cytochrome P450 2E1) plus tumor necrosis factor alpha treatment occurs in c-Jun N-terminal kinase 2−/− but not in c-Jun N-terminal kinase 1 −/− mice
Authors: Wang Xiaodong , Wu Defeng , Yang Lili , Cederbaum Arthur I.
Published: July 2011

Cytochrome P450 2E1 (CYP2E1) induction and tumor necrosis factor alpha (TNF-α) production are key risk factors in alcoholic liver injury. Increased oxidative stress from CYP2E1 induction by pyrazole in vivo sensitizes the liver to TNF-α-induced hepatotoxicity by a mechanism involving the activation of c-jun N-terminal kinase (JNK) and mitochondrial damage. The aim of this study was to evaluate whether JNK1 or JNK2 plays a role in this potentiated hepatotoxicity. Wild-type (WT), jnk1
−/−, and jnk2
−/− mice were used to identify changes of hepatotoxicity, damage to mitochondria, and production of oxidative stress after pyrazole plus TNF-α treatment. Increased serum alanine aminotransferase, inflammatory infiltration, and central necrosis were observed in the jnk2−/− and WT mice treated with pyrazole plus TNF-α, but not in the jnk1
−/− mice. Pyrazole elevated the activity and protein level of CYP2E1 in all mice. There was a significant increase of malondialdehyde, 4-hydroxynonenal adducts, 3-nitrotyrosine, and inducible nitric oxide synthase in the jnk2
−/− and WT mice, compared to the jnk1
−/− mice, upon pyrazole plus TNF-α treatment, or compared to mice treated with either pyrazole alone or TNF-α alone. The antioxidants, catalase, phospholipid hydroperoxide glutathione peroxidase, thioredoxin, and glutathione were lowered, and cytochrome c was released from the mitochondria in the jnk2
−/− and WT mice. Mitochondrial production of superoxide was increased in the jnk2
−/− and WT mice, compared to the jnk1
−/− mice, upon pyrazole plus TNF-α treatment. Electron microscopy showed altered mitochondrial structure in the jnk2
−/− and WT mice, but not the jnk1
−/− mice. Conclusions: JNK1 plays a role in the hepatotoxicity, mitochondrial dysfunction, and oxidative stress mediated by pyrazole plus TNF-α treatment. These findings raise the question as to the potential mechanisms of JNK1 activation related to alcoholic liver injury. (Hepatology 2011;)
Human leukocyte antigen B27 selects for rare escape mutations that significantly impair hepatitis C virus replication and require compensatory mutations
Authors: Neumann-Haefelin Christoph , Oniangue-Ndza Cesar , Kuntzen Thomas , Schmidt Julia , Nitschke Katja , Sidney John , Caillet-Saguy Célia , Binder Marco , Kersting Nadine , Kemper Michael W. , Power Karen A. , Ingber Susan , Reyor Laura L. , Hills-Evans Kelsey , Kim Arthur Y. , Lauer Georg M. , Lohmann Volker , Sette Alessandro , Henn Matthew R. , Bressanelli Stéphane , Thimme Robert , Allen Todd M.
Published: July 2011

Human leukocyte antigen B27 is associated with spontaneous viral clearance in hepatitis C virus (HCV) infection. Viral escape within the immunodominant, HLA-B27-restricted, HCV-specific, cluster of differentiation (CD)8+ T-cell epitope, nonstructural protein (NS)5B2841-2849 (ARMILMTHF), has been shown to be limited by viral fitness costs as well as broad T-cell cross-recognition, suggesting a potential mechanism of protection by HLA-B27. Here, we studied the subdominant HLA-B27-restricted epitope, NS5B2936-2944 (GRAAICGKY), to further define the mechanisms of protection by HLA-B27. We identified a unique pattern of escape mutations within this epitope in a large cohort of HCV genotype 1a–infected patients. The predominant escape mutations represented conservative substitutions at the main HLA-B27 anchor residue or a T-cell receptor contact site, neither of which impaired viral replication capacity, as assessed in a subgenomic HCV replicon system. In contrast, however, in a subset of HLA-B27+ subjects, rare escape mutations arose at the HLA-B27 anchor residue, R2937, which nearly abolished viral replication. Notably, these rare mutations only occurred in conjunction with the selection of two equally rare, and structurally proximal, upstream mutations. Coexpression of these upstream mutations with the rare escape mutations dramatically restored viral replication capacity from <5% to ≥70% of wild-type levels.

Conclusion:

The selection of rare CTL escape mutations in this HLA-B27-restricted epitope dramatically impairs viral replicative fitness, unless properly compensated. These data support a role for the targeting of highly constrained regions by HLA-B27 in its ability to assert immune control of HCV and other highly variable pathogens. (Hepatology 2011;)
Promotion of tumor cell metastasis and vasculogenic mimicry by way of transcription coactivation by Bcl-2 and Twist1: A study of hepatocellular carcinoma
Authors: Sun Tao , Sun Bao-cun , Zhao Xiu-lan , Zhao Nan , Dong Xue-yi , Che Na , Yao Zhi , Ma Yue-mei , Gu Qiang , Zong Wen-kang , Liu Zhi-yong
Published: July 2011

The antiapoptotic protein Bcl-2 plays multiple roles in apoptosis, immunity, and autophagy. Its expression in tumors correlates with tumor grade and malignancy. The recapitulation of the normal developmental process of epithelial-mesenchymal transition (EMT) contributes to tumor cell plasticity. This process is also a characteristic of metastatic cells and vasculogenic mimicry. In the present study we report functional and structural interactions between Bcl-2 and the EMT-regulating transcription factor Twist1 and the relationship with metastasis and vascular mimicry. Bcl-2 and Twist1 are coexpressed under hypoxia conditions. The Bcl-2 can bind to Twist1 in vivo and in vitro. This interaction involves basic helix-loop-helix DNA binding domain within Twist1 and through two separate domains within Bcl-2 protein. Formation of the Bcl-2/Twist1 complex facilitates the nuclear transport of Twist1 and leads to transcriptional activation of wide ranges of genes that can increase the tumor cell plasticity, metastasis, and vasculogenic mimicry. Finally, nuclear expression of Bcl-2 and Twist1 is correlated with poor survival of these patients in a cohort of 97 cases of human hepatocellular carcinoma. Conclusion: The results describe a novel function of Bcl-2 in EMT induction, provide insight into tumor progression, and implicate the Bcl-2/Twist1 complex as a potential target for developing chemotherapeutics. (Hepatology 2011;)
Pentoxifylline improves nonalcoholic steatohepatitis: A randomized placebo-controlled trial
Authors: Zein Claudia O. , Yerian Lisa M. , Gogate Prema , Lopez Rocio , Kirwan John P. , Feldstein Ariel E. , McCullough Arthur J.
Published: July 2011

The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of nonalcoholic steatohepatitis (NASH). In all, 55 adults with biopsy-confirmed NASH were randomized to receive PTX at a dose of 400 mg three times a day (n = 26) or placebo (n = 29) over 1 year. The primary efficacy endpoint was defined as improvement in histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ≥2 points in the nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 1 year, intention-to-treat analysis showed a decrease of ≥2 points in the NAS in 38.5% of patients on PTX versus 13.8% of those on placebo (P = 0.036). Per protocol analysis, a decrease of ≥2 points in the NAS from baseline was observed in 50% of the patients on PTX versus 15.4% of those on placebo (P = 0.01). The mean change in NAS score from baseline was −1.6 in the PTX group, versus −0.1 in the placebo group (P < 0.001). PTX significantly improved steatosis (mean change in score −0.9 versus −0.04 with placebo, P < 0.001) and lobular inflammation (median change −1 versus 0 with placebo, P = 0.02). No significant effects in hepatocellular ballooning were observed. PTX also improved liver fibrosis (mean change in fibrosis score was −0.2 among those on PTX versus +0.4 among those on placebo, P = 0.038). Although not statistically significant (P = 0.17), improvement in fibrosis was observed in a greater proportion (35%) of patients in the PTX group compared to placebo (15%). Adverse effects were similar in both groups. Conclusion: PTX improved histological features of NASH compared to placebo. PTX was well tolerated in patients with NASH (ClinicalTrials.gov number NCT00590161). (Hepatology 2011)
Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: A randomized trial comparing 3- and 6-month periodicities
Authors: Trinchet Jean-Claude , Chaffaut Cendrine , Bourcier Valérie , Degos Françoise , Henrion Jean , Fontaine Hélène , Roulot Dominique , Mallat Ariane , Hillaire Sophie , Cales Paul , Ollivier Isabelle , Vinel Jean-Pierre , Mathurin Philippe , Bronowicki Jean-Pierre , Vilgrain Valérie , N'Kontchou Gisèle , Beaugrand Michel , Chevret Sylvie
Published: July 2011

Detection of small hepatocellular carcinoma (HCC) eligible for curative treatment is increased by surveillance, but its optimal periodicity is still debated. Thus, this randomized trial compared two ultrasonographic (US) periodicities: 3 months versus 6 months. A multicenter randomized trial was conducted in France and Belgium (43 sites). Patients with histologically proven compensated cirrhosis were randomized into two groups: US every 6 months (Gr6M) or 3 months (Gr3M). For each focal lesion detected, diagnostic procedures were performed according to European Association for the Study of the Liver guidelines. Cumulative incidence of events was estimated, then compared using Gray's test. The prevalence of HCC ≤30 mm in diameter was the main endpoint. A sample size of 1,200 patients was required. A total of 1,278 patients were randomized (Gr3M, n = 640; Gr6M, n = 638; alcohol 39.2%, hepatitis C virus 44.1%, hepatitis B virus 12.5%). At least one focal lesion was detected in 358 patients (28%) but HCC was confirmed in only 123 (9.6%) (uninodular 58.5%, ≤30 mm in diameter 74%). Focal-lesion incidence was not different between Gr3M and Gr6M groups (2-year estimates, 20.4% versus 13.2%,

P

= 0.067) but incidence of lesions ≤10 mm was increased (41% in Gr3M versus 28% in Gr6M,

P

= 0.002). No difference in either HCC incidence (

P

= 0.13) or in prevalence of tumors ≤30 mm in diameter (79% versus 70%,

P

= 0.30) was observed between the randomized groups.

Conclusion:

US surveillance, performed every 3 months, detects more small focal lesions than US every 6 months, but does not improve detection of small HCC, probably because of limitations in recall procedures. (Hepatology 2011;)
Impact of IL28B on treatment outcome in hepatitis C virus G1/4 patients receiving response-guided therapy with peginterferon alpha-2a (40KD)/ribavirin
Authors: Scherzer Thomas-Matthias , Stättermayer Albert Friedrich , Strasser Michael , Laferl Hermann , Maieron Andreas , Stauber Rudolf , Datz Christian , Dulic-Lakovic Emina , Steindl-Munda Petra , Hofer Harald , Ferenci Peter
Published: July 2011

The IL28B genotype is the most important pretreatment predictor of treatment outcome in patients with chronic hepatitis C. The impact of the rs12979860 genotype on relapse was retrospectively evaluated in genotype 1/4 patients who received response-guided therapy with peginterferon alpha-2a 180 μg/week plus ribavirin 1,000/1,200 mg/day in a large, randomized, multicenter study. Patients with a rapid virologic response (RVR: hepatitis C virus [HCV] RNA <50 IU/mL) at week 4 were treated for 24 weeks; those with a slow virologic response (no RVR but undetectable HCV RNA or ≥2-log10 decrease at week 12) were randomized to 48 (group A) or 72 weeks of treatment (group B). Relapse rates were compared by rs12979860 genotype (C/C versus combined T/C or T/T [T/*]) in patients with confirmed end-of-treatment response and known end-of-follow-up status (sustained virologic response [SVR] or relapse). The rs12979860 genotype was determined for 340/551 study participants. In patients with RVR and C/C or T/* genotype, relapse rates were similar (10.7% versus 15.2%). In patients randomized to groups A and B, relapse rates were similar in patients with C/C genotype randomized to group A (26.9%) and group B (20.0%). In contrast, relapse rates in T/* patients differed markedly between groups A and B, overall (42.9% and 18.8%; P < 0.025, respectively) and in those with low (<400,000 IU/mL: 37.5% versus 18.8%) and high (≥400,000 IU/mL: 45.0% versus 18.8%) baseline viral loads. Conclusion: The results suggest that the benefits of extended therapy are restricted to patients with a T allele. Relapse rates are highest in patients with T/* genotype and are markedly higher in slow responders treated for 48 weeks compared with 72 weeks. (Hepatology 2011;)
Type 2 inositol 1,4,5-trisphosphate receptor modulates bile salt export pump activity in rat hepatocytes
Authors: Kruglov Emma A. , Gautam Samir , Guerra Mateus T. , Nathanson Michael H.
Published: July 2011

Bile salt secretion is mediated primarily by the bile salt export pump (Bsep), a transporter on the canalicular membrane of the hepatocyte. However, little is known about the short-term regulation of Bsep activity. Ca2+ regulates targeting and insertion of transporters in many cell systems, and Ca2+ release near the canalicular membrane is mediated by the type II inositol 1,4,5-trisphosphate receptor (InsP3R2), so we investigated the possible role of InsP3R2 in modulating Bsep activity. The kinetics of Bsep activity were monitored by following secretion of the fluorescent Bsep substrate cholylglycylamido-fluorescein (CGamF) in rat hepatocytes in collagen sandwich culture, an isolated cell system in which structural and functional polarity is preserved. CGamF secretion was nearly eliminated in cells treated with Bsep small interfering RNA (siRNA), demonstrating specificity of this substrate for Bsep. Secretion was also reduced after chelating intracellular calcium, inducing redistribution of InsP3R2 by depleting the cell membrane of cholesterol, or reducing InsP3R function by either knocking down InsP3R2 expression using siRNA or pharmacologic inhibition using xestospongin C. Confocal immunofluorescence showed that InsP3R2 and Bsep are in close proximity in the canalicular region, both in rat liver and in hepatocytes in sandwich culture. However, after knocking down InsP3R2 or inducing its dysfunction with cholesterol depletion, Bsep redistributed intracellularly. Finally, InsP3R2 was lost from the pericanalicular region in animal models of estrogen- and endotoxin-induced cholestasis. Conclusion: These data provide evidence that pericanalicular calcium signaling mediated by InsP3R2 plays an important role in maintaining bile salt secretion through posttranslational regulation of Bsep, and suggest that loss or redistribution of InsP3R2 may contribute to the pathophysiology of intrahepatic cholestasis. (Hepatology 2011;)
Predicting clinical outcomes using baseline and follow-up laboratory data from the hepatitis C long-term treatment against cirrhosis trial
Authors: Ghany Marc G. , Kim Hae-Young , Stoddard Anne , Wright Elizabeth C. , Seeff Leonard B. , Lok Anna S.F.
Published: July 2011

Predicting clinical outcomes in patients with chronic hepatitis C is challenging. We used the hepatitis C long-term treatment against cirrhosis (HALT-C) trial database to develop two models, using baseline values of routinely available laboratory tests together with changes in these values during follow-up to predict clinical decompensation and liver-related death/liver transplant in patients with advanced hepatitis C. Patients randomized to no treatment and who had ≥2-year follow-up without a clinical outcome were included in the analysis. Four variables (platelet count, aspartate aminotransferase [AST]/alanine aminotransferase [ALT] ratio, total bilirubin, and albumin) with three categories of change (stable, mild, or severe) over 2 years were analyzed. Cumulative incidence of clinical outcome was determined by Kaplan-Meier analysis and Cox regression was used to evaluate predictors of clinical outcome. In all, 470 patients with 60 events were used to develop models to predict clinical decompensation. Baseline values of all four variables were predictive of decompensation. There was a general trend of increasing outcomes with more marked worsening of laboratory values over 2 years, particularly for patients with abnormal baseline values. A model that included baseline platelet count, AST/ALT ratio, bilirubin, and severe worsening of platelet count, bilirubin, and albumin was the best predictor of clinical decompensation. A total of 483 patients with 79 events were used to evaluate predictors of liver-related death or liver transplant. A model that included baseline platelet count and albumin as well as severe worsening of AST/ALT ratio and albumin was the best predictor of liver-related outcomes. Conclusion: Both the baseline value and the rapidity in change of the value of routine laboratory variables were shown to be important in predicting clinical outcomes in patients with advanced chronic hepatitis C. (Hepatology 2011;)
Shorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C
Authors: Liaw Y.-F. , Jia J.-D. , Chan H. L.Y. , Han K. H. , Tanwandee T. , Chuang W. L. , Tan D. M. , Chen X. Y. , Gane E. , Piratvisuth T. , Chen L. , Xie Q. , Sung J. J.Y. , Wat C. , Bernaards C. , Cui Y. , Marcellin P.
Published: July 2011

As there is currently a lack of consensus on the most appropriate dose and duration of peginterferon alfa-2a (PEG-IFNα-2a) therapy in hepatitis B e antigen (HBeAg)-positive patients, the efficacy and safety of either 24 or 48 weeks' duration and 90 μg/week or 180 μg/week doses were compared. HBeAg-positive patients (n = 544; 34% genotype B, 51% genotype C) were randomized to receive PEG-IFNα-2a (2 × 2 factorial design) for 24 or 48 weeks and at 90 μg/week or 180 μg/week and included in the per-protocol population. The primary efficacy endpoint of the noninferiority study was HBeAg seroconversion 6 months posttreatment. The prespecified odds ratio (OR) noninferiority margin was 1.88 with a one-sided significance level of 0.025. The highest rates of HBeAg seroconversion 6 months posttreatment were in the 180/48 arm (36.2% versus 14.1%-25.8% in the other arms). When the dose and duration arms were pooled, the OR for noninferiority of 24 weeks versus 48 weeks was 2.17 (95% confidence interval [CI] 1.43, 3.31; P = 0.749) and for 90 μg versus 180 μg was 1.79 (95% CI 1.18, 2.72; P = 0.410). As the upper limit of the 95% CI of the ORs were >1.88, 24 weeks were inferior to 48 weeks and 90 μg/week was inferior to 180 μg/week. The highest rates of response in the 180/48 arm were achieved by patients with HBsAg <1,500 IU/mL at Week 12 (58%) or Week 24 (57%), whereas patients with HBsAg >20,000 IU/mL did not respond. Adverse events were typical of those associated with PEG-IFNα-2a. Conclusion: Compared with lower doses and shorter durations, the licensed PEG-IFNα-2a treatment regimen (180μg/48 weeks) was the most efficacious and beneficial for HBeAg-positive patients predominantly infected with hepatitis B virus genotypes B or C. (Hepatology 2011;)
Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C
Authors: Golden-Mason Lucy , Bambha Kiran M. , Cheng Linling , Howell Charles D. , Taylor Milton W. , Clark Paul J. , Afdhal Nezam , Rosen Hugo R.
Published: July 2011

Natural killer (NK) cells constitute a first line of defense against viral infections; their function is governed by the integration of signals from multiple activating and inhibitory surface receptors. We hypothesized that because NKs become rapidly activated by cytokines, response to anti-hepatitis C virus (HCV) therapy would be predicted by the phenotype and function of NKs. We used a cohort of 101 patients (55 African, 46 Caucasian-American) who received pegylated-interferon (IFN) and ribavirin for 48 weeks. Multiparameter FACS analysis was used to examine relative expression of 14 different inhibitory/activating receptors. Interleukin (IL)-28B genotyping (rs12979860) was also performed. Pretreatment levels of inhibitory receptors CD158a, CD158b, and CD158e were higher in patients who demonstrated poor viral decline within the first 28 days of therapy. Higher expression levels of inhibitory receptors NKG2A, CD158b, and CD158e were demonstrable in patients who failed to achieve sustained virologic response (SVR). Patients carrying the IL-28B T allele had higher NKG2A expression on effector NKs. We created a mathematical regression model incorporating race, viral level, and two inhibitory receptors. The area-under-the curve was 0.88, which is highly predictive of SVR. Moreover, the model performed complementarily with IL-28B across the CC, CT, and TT genotypes. Purified NKG2Aneg NKs treated with pegylated-IFN-α for 4 hours demonstrated higher levels of IFN-γ-inducible protein-10 (IP-10) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) compared with their NKG2Apos counterparts. Conclusions: These results provide novel insights into the associations of NK phenotype with IL-28B genotype and gene expression patterns, as well as the role of NKs in mediating IFN-induced viral clearance of chronic HCV infection. (Hepatology 2011;)