bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bile salt–induced pro-oxidant liver damage promotes transplanted cell proliferation for correcting Wilson disease in the Long-Evans Cinnamon rat model #
Authors: Joseph Brigid , Kapoor Sorabh , Schilsky Michael L. , Gupta Sanjeev 
Published: December 2008

Abstract
Insights into disease-specific mechanisms for liver repopulation are needed for cell therapy. To understand the efficacy of pro-oxidant hepatic perturbations in Wilson disease, we studied Long-Evans Cinnamon (LEC) rats with copper toxicosis under several conditions. Hepatocytes from healthy Long-Evans Agouti (LEA) rats were transplanted intrasplenically into the liver. A cure was defined as lowering of copper to below 250 μg/g liver, presence of ATPase, Cu++ transporting, beta polypeptide (atp7b) messenger RNA (mRNA) in the liver and improvement in liver histology. Treatment of animals with the hydrophobic bile salt, cholic acid, or liver radiation before cell transplantation produced cure rates of 14% and 33%, respectively; whereas liver radiation plus partial hepatectomy followed by cell transplantation proved more effective, with cure in 55%, P < 0.01; and liver radiation plus cholic acid followed by cell transplantation was most effective, with cure in 75%, P < 0.001. As a group, cell therapy cures in rats preconditioned with liver radiation plus cholic acid resulted in less hepatic copper, indicating greater extent of liver repopulation. We observed increased hepatic catalase and superoxide dismutase activities in LEC rats, suggesting chronic oxidative stress. After liver radiation or cholic acid, hepatic lipid peroxidation levels increased, indicating further oxidative injury, although we did not observe overt additional cytotoxicity. This contrasted with healthy animals in which liver radiation and cholic acid produced hepatic steatosis and loss of injured hepatocytes. We concluded that pro-oxidant perturbations were uniquely effective for cell therapy in Wilson disease because of the nature of preexisting hepatic damage. (Hepatology 2009.)
Association between hypothyroidism and hepatocellular carcinoma: A case-control study in the United States #
Authors: Hassan Manal M. , Kaseb Ahmed , Li Donghui , Patt Yehuda Z. , Vauthey Jean-Nicolas , Thomas Melanie B. , Curley Steven A. , Spitz Margaret R. , Sherman Steven I. , Abdalla Eddie K. , Davila Marta , Lozano Richard D. , Hassan Deena M. , Chan Wenyaw , Brown Thomas D. , Abbruzzese James L. 
Published: December 2008

Abstract
Thyroid hormones play an essential role in lipid mobilization, lipid degradation, and fatty acid oxidation. Hypothyroidism has been associated with nonalcoholic steatohepatitis; however, the association between thyroid diseases and hepatocellular carcinoma (HCC) in men and women has not been well established. We investigated the association between hypothyroidism and HCC risk in men and women in a case-control study, which included 420 eligible patients with HCC and 1104 healthy controls. We used multivariate unconditional logistic regression models to control for the confounding effects of established HCC risk factors. A long-term history of hypothyroidism (>10 years) was associated with a statistically significant high risk of HCC in women; after adjusting for demographic factors, diabetes, hepatitis, alcohol consumption, cigarette smoking, and family history of cancer, the odds ratio (OR) was 2.9 (95% confidence interval [CI], 1.3-6.3). Restricted analyses among hepatitis virus–negative subjects, nondrinkers, nondiabetics, nonsmokers, and nonobese individuals indicated a significant association between hypothyroidism and HCC, with an approximate two-fold to three-fold increased risk of HCC development. We observed risk modification among women with diabetes mellitus (OR = 9.4; 95% CI = 2.7-32.7) and chronic hepatitis virus infection (OR = 31.2; 95% CI = 6.3-153.2). A history of hyperthyroidism was not significantly related to HCC (OR = 1.7; CI = 0.6-5.1). We noted significant elevated risk association between hypothyroidism and HCC in women that was independent of established HCC risk factors. Experimental investigations are necessary for thorough assessment of the relationship between thyroid disorders and HCC. (Hepatology 2009;49:1563–1570.)
HBV superinfection in HCV chronic carriers: A disease that is frequently severe but associated with the eradication of HCV #
Authors: Sagnelli Evangelista , Coppola Nicola , Pisaturo Mariantonietta , Masiello Addolorata , Tonziello Gilda , Sagnelli Caterina , Messina Vincenzo , Filippini Pietro 
Published: December 2008

Abstract
The impact of hepatitis B virus (HBV) superinfection in hepatitis C virus (HCV) chronic carriers was evaluated in a long-term follow-up study on 29 chronic anti-HCV carriers with acute hepatitis B (AVH-B) (Case group BC) and 29 anti-HCV negative patients with AVH-B (Control group B), pair-matched for age (±5 years), sex, and risk factors for the acquisition of HBV infection. Patients in Case group BC and those in Control group B showed similar initial HBV viral load and a similar trend of becoming negative for HBV-DNA. AVH-B showed a severe course more frequently in Case group BC than in Control group B (34.5% versus 6.9%, P < 0.05). Of the 28 patients in Case group BC alive at the end of the acute illness (one death from liver failure), 24 were followed up for 2-6 years, median 5 years: 22 patients became HBsAg-negative and two progressed to HBsAg-positive chronic hepatitis. HCV-RNA was undetectable in all patients during AVH-B; in the 24 patients with a long-term follow-up, HCV-RNA was detected in seven (29.2%) after 1 year, in 14 (58.3%) after 2 years, and in 18 (75%) after 3-6 years. The six patients who eradicated chronic HCV infection, compared with 18 showing reactivation of HCV replication, had higher values of aspartate aminotransferase and alanine aminotransferase and a higher prevalence of cases with severe AVH-B (83.3% versus 22.2%, P < 0.05). Conclusions: Although it can be life-threatening, HBV superinfection in HCV chronic carriers may lead to clearance of chronic HCV infection, especially in patients with severe AVH-B. (Hepatology 2009.)
Efficacy of hepatitis B vaccine against antiviral drug-resistant hepatitis B virus mutants in the chimpanzee model #
Authors: Kamili Saleem , Sozzi Vitini , Thompson Geoff , Campbell Katie , Walker Christopher M. , Locarnini Stephen , Krawczynski Krzysztof 
Published: December 2008

Abstract
Hepatitis B virus (HBV) mutants resistant to treatment with nucleoside or nucleotide analogs and those with the ability to escape from HBV-neutralizing antibody have the potential to infect HBV-vaccinated individuals. To address this potential serious public health challenge, we tested the efficacy of immunity induced by a commercial hepatitis B vaccine against a tissue culture-derived, clonal HBV polymerase mutant in HBV seronegative chimpanzees. The polymerase gene mutant contained a combination of three mutations (rtV173L, rtL180M, rtM204V), two of which resulted in changes to the overlapping viral envelope of the hepatitis B surface antigen (sE164D, sI195M). Prior to the HBV mutant challenge of vaccinated chimpanzees, we established virologic, serologic, and pathologic characteristics of infections resulting from intravenous inoculation of the HBV polymerase gene mutant and the sG145R vaccine-escape surface gene mutant. Cloning and sequencing experiments determined that the three mutations in the polymerase gene mutant remained stable and that the single mutation in the surface gene mutant reverted to the wild-type sequence. Immunological evidence of HBV replication was observed in the vaccinated chimpanzees after challenge with the polymerase gene mutant as well as after rechallenge with serum-derived wild-type HBV (5,000 chimpanzee infectious doses administered intravenously), despite robust humoral and cellular anti-HBV immune responses after hepatitis B vaccination. Conclusion: Our data showing successful experimental infection by HBV mutants despite the presence of high anti-HBs levels considered protective in the vaccinated host are consistent with clinical reports on breakthrough infection in anti-HBs-positive patients infected with HBV mutants. In the absence of a protective humoral immunity, adaptive cellular immune responses elicited by infection may limit HBV replication and persistence. (Hepatology 2009.)
Changes in stream water quality due to logging of the boreal forest in the Montmorency Forest, Québec
Authors: Tremblay Yohann , Rousseau Alain N. , Plamondon André P. , Lévesque Denis , Prévost Marcel 
Published: December 2008

AbstractSummer stream water quality was monitored before and following the logging of 50% of the boreal forest within three small watersheds (<50 ha) nested in the ‘Ruisseau des Eaux‐Volées’ Experimental Watershed, Montmorency Forest (Québec, Canada). Logging was conducted in winter, on snow cover according to recommended best management practices (BMPs) to minimize soil disturbance and protect advance growth. A 20‐m forest buffer was maintained along perennial streams. In watershed 7·2, cut‐blocks were located near the stream network and logging was partially allowed within the riparian buffer zone. In watersheds 7·5 and 7·7, logging occurred farther away from the stream network. Observations were also made for watershed 7·3 that collected the runoff from watersheds 7·2 and 7·5, and watershed 7·6, the uproad portion of watershed 7·7. The control watershed 0·2 was contiguous to the impacted watersheds and remained undisturbed. Following clearcutting, changes in summer daily maximum and minimum stream temperatures remained within ± 1 °C while changes in diurnal variation did not decrease by more than 0·5 °C. Concentrations of NO3− greatly increased by up to 6000% and concentrations of K+ increased by up to 300% during the second summer after logging. Smaller increases were observed for Fetotal (up to 71%), specific conductance (up to 26%), and Mg2+ (up to 19%). Post‐logging pH decreased slightly by no more than 7% while PO43− concentration remained relatively constant. Suspended sediment concentrations appeared to increase during post‐logging, but there was not enough pre‐logging data to statistically confirm this result. Logging of moderate intensity and respecting established BMPs may account for the limited changes of water quality parameters and the low exceedances of the criteria for the protection of aquatic life. The proximity of the cutover to the stream network and logging within the riparian zone did not appear to affect water quality. Copyright © 2008 John Wiley & Sons, Ltd.
Large genomic rearrangements and germline epimutations in Lynch syndrome
Authors: Gylling Annette , Ridanpää Maaret , Vierimaa Outi , Aittomäki Kristiina , Avela Kristiina , Kääriäinen Helena , Laivuori Hannele , Pöyhönen Minna , Sallinen Satu‐Leena , Wallgren‐Pettersson Carina , Järvinen Heikki J. , Mecklin Jukka‐Pekka , Peltomäki Paivi 
Published: December 2008

AbstractIn one‐third of families fulfilling the Amsterdam criteria for hereditary nonpolyposis colorectal cancer/Lynch syndrome, and a majority of those not fulfilling these criteria point mutations in DNA mismatch repair (MMR) genes are not found. The role of large genomic rearrangements and germline epimutations in MLH1, MSH2 and MSH6 was evaluated in 2 such cohorts. All 45 index patients were mutation‐negative by genomic sequencing and testing for a prevalent population‐specific founder mutation, and selectively lacked MMR protein expression in tumor tissue. Eleven patients (“research cohort”) represented 11 mutation‐negative families among 81 verified or putative Lynch syndrome families from the nation‐wide Hereditary Colorectal Cancer Registry of Finland. Thirty‐four patients from 33 families (“clinic‐based cohort”) represented suspected Lynch syndrome patients tested for MMR gene mutations in a diagnostic laboratory during 2004–2007. Multiplex ligation‐dependent probe amplification (MLPA) and methylation‐specific (MS)‐MLPA were used to detect rearrangements and epimutations, respectively. Large genomic deletions occurred in 12/45 patients (27%), being present in 3/25 (12%), 9/16 (56%) and 0/4 (0%) among index patients lacking MLH1, MSH2 or MSH6 expression, respectively. Germline epimutations of MLH1, one of which coexisted with a genomic deletion, occurred in 2 patients (4%) and were accompanied by monoallelic expression in mRNA. Large genomic deletions (mainly MSH2) and germline epimutations (MLH1) together explain a significant fraction of point mutation‐negative families suspected of Lynch syndrome and are associated with characteristic clinical and family features. Our findings have important implications in the diagnosis and management of such families. © 2008 Wiley‐Liss, Inc.
The mannose 6‐phosphate/insulin‐like growth factor II receptor restricts the tumourigenicity and invasiveness of squamous cell carcinoma cells
Authors: Probst Olivia C. , Puxbaum Verena , Svoboda Barbara , Leksa Vladimir , Stockinger Hannes , Mikula Mario , Mikulits Wolfgang , Mach Lukas 
Published: December 2008

AbstractThe mannose 6‐phosphate/insulin‐like growth factor II receptor (M6P/IGF2R) mediates biosynthetic sorting and endocytosis of various factors that impinge on the proliferation, migration and invasiveness of tumour cells. The gene encoding M6P/IGF2R is frequently lost or mutated in a wide range of malignant tumours including squamous cell carcinomas. We have previously shown that M6P/IGF2R‐deficient SCC‐VII murine squamous cell carcinoma cells secrete large amounts of pro‐invasive lysosomal proteinases. Furthermore, the formation of mature lysosomes is impaired in SCC‐VII cells. To assess the link between M6P/IGF2R status and tumour invasion, we have now generated SCC‐VII lines stably transfected with human M6P/IGF2R cDNA. Reconstitution of functional M6P/IGF2R expression in SCC‐VII cells strongly improves the intracellular retention of lysosomal proteinases and restores the formation of mature lysosomes. In addition, the presence of heterologous M6P/IGF2R compromises the growth of SCC‐VII cells both in vitro and in vivo. Remarkably, M6P/IGF2R expression also reduces the invasive capacity of SCC‐VII cells in response to various chemoattractants. These results indicate that the M6P/IGF2R status influences the metastatic propensity of squamous cell carcinomas. © 2008 Wiley‐Liss, Inc.
Endometrial cancer invasion depends on cancer‐derived tumor necrosis factor‐α and stromal derived hepatocyte growth factor
Authors: Choi Dong Soon , Kim Hyun‐Jin , Yoon Jong‐Hyuck , Yoo Seung‐Chul , Jo Hantae , Lee So Yeon , Min Churl K. , Ryu Hee‐Sug 
Published: December 2008

AbstractCancer invasion is an outcome of interactions of the cancer and the host cell. It is now becoming increasingly clear that ovarian hormones have a huge influence on such intercommunications in various types of cancers. Estrogen is known to aggravate the aggressiveness of the endometrial cancer whereas progesterone seems to act as a negative factor. Insight into the mode of ovarian hormonal actions could come from the studies of its regulation of the paracrine interactions between the endometrial cancer and the normal stromal cells during the cancer invasion. In this context, we report here that estrogen promotes the endometrial cancer invasion by inducing humoral interactions between the cancer and the stromal cells, i.e., estrogen stimulates tumor necrosis factor‐α expression from the endometrial cancer cells, which, in turn, induces the stromal expression of hepatocyte growth factor (HGF), conferring the enhanced NK4 (HGF‐antagonist/angiogenesis inhibitor)‐sensitive invasion characteristic of the endometrial cancer cells. Additionally, we demonstrate a close correlation of the invasion of endometrial cancer cells with the expression and dimerization of integrin αvβ5 as well as the activation of focal adhesion kinase as the consequences of paracrine interactions. Thus, understanding of paracrine interactions of cancer cells with host stromal cells can yield new insight into the architecture and function of cancer invasion and metastasis, leading to a development of a new cancer therapeutic intervention. © 2008 Wiley‐Liss, Inc.
Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule‐dependency
Authors: Mikkelsen Tom , Brodie Chaya , Finniss Susan , Berens Michael E. , Rennert Jessica L. , Nelson Kevin , Lemke Nancy , Brown Stephen L. , Hahn Diane , Neuteboom Berend , Goodman Simon L. 
Published: December 2008

AbstractWe investigated whether cilengitide could amplify the antitumor effects of radiotherapy in an orthotopic rat glioma xenograft model. Cilengitide is a specific inhibitor of αv series integrins, and acts as an antiangiogenic. U251 human glioma cells express αvβ3 and αvβ5 integrins. We used in vitro assays of adhesion and growth of tumor and endothelial cells to evaluate cytotoxicity and the potential for cilengitide to enhance radiation toxicity. Treatment was then evaluated in an orthotopic model to evaluate synergy with therapeutic radiation in vivo. In vitro, cilengitide blocked cell adhesion, but did not influence the effects of radiation on U251 cells; cilengitide strongly amplified radiation effects on endothelial cell survival. In vivo, radiotherapy prolonged the survival of U251 tumor‐bearing rats from 50 to over 110 days. Cotreatment with cilengitide and radiation dramatically amplified the effects of radiation, producing survival over 200 days and triggering an enhanced apoptotic response and suppression of tumor growth by histology at necropsy. Signaling pathways activated in the tumor included NFκb, a documented mediator of cellular response to radiation. Because cilengitide has a short plasma half‐life (t½ ∼ 20 min), antiangiogenic scheduling typically uses daily injections. We found that a single dose of cilengitide (4 mg/kg) given between 4 and 12 hr prior to radiation was sufficient to produce the same effect. Our results demonstrate that blockade of αv integrins mediates an unanticipated rapid potentiation of radiation, and suggests possible clinical translation for glioma therapy. © 2008 Wiley‐Liss, Inc.
Induction of myeloid‐derived suppressor cells by tumor exosomes
Authors: Xiang Xiaoyu , Poliakov Anton , Liu Cunren , Liu Yuelong , Deng Zhong‐bin , Wang Jianhua , Cheng Ziqiang , Shah Spandan V. , Wang Gui‐Jun , Zhang Liming , Grizzle William E. , Mobley Jim , Zhang Huang‐Ge 
Published: December 2008

AbstractMyeloid‐derived suppressor cells (MDSCs) promote tumor progression. The mechanisms of MDSC development during tumor growth remain unknown. Tumor exosomes (T‐exosomes) have been implicated to play a role in immune regulation, however the role of exosomes in the induction of MDSCs is unclear. Our previous work demonstrated that exosomes isolated from tumor cells are taken up by bone marrow myeloid cells. Here, we extend those findings showing that exosomes isolated from T‐exosomes switch the differentiation pathway of these myeloid cells to the MDSC pathway (CD11b+Gr‐1+). The resulting cells exhibit MDSC phenotypic and functional characteristics including promotion of tumor growth. Furthermore, we demonstrated that in vivo MDSC mediated promotion of tumor progression is dependent on T‐exosome prostaglandin E2 (PGE2) and TGF‐β molecules. T‐exosomes can induce the accumulation of MDSCs expressing Cox2, IL‐6, VEGF, and arginase‐1. Antibodies against exosomal PGE2 and TGF‐β block the activity of these exosomes on MDSC induction and therefore attenuate MDSC‐mediated tumor‐promoting ability. Exosomal PGE2 and TGF‐β are enriched in T‐exosomes when compared with exosomes isolated from the supernatants of cultured tumor cells (C‐exosomes). The tumor microenvironment has an effect on the potency of T‐exosome mediated induction of MDSCs by regulating the sorting and the amount of exosomal PGE2 and TGF‐β available. Together, these findings lend themselves to developing specific targetable therapeutic strategies to reduce or eliminate MDSC‐induced immunosuppression and hence enhance host antitumor immunotherapy efficacy. © 2008 Wiley‐Liss, Inc.
Correlation between rate of bony ingrowth to stainless steel, pure titanium, and titanium alloy implants in vivo and formation of hydroxyapetite on their surfaces in vitro
Authors: Oron A. , Agar G. , Oron U. , Stein A. 
Published: December 2008

AbstractThe rate of bony ingrowth to identical metal implants made of either pure titanium (cpTi), titanium alloy (Ti‐6Al‐4V), or stainless steel 316L (SS) inserted to the medullar canal of the femur in rats was investigated. The kinetics of spontaneous deposition of hydroxyapatite (HA) globules on the aforementioned metals in vitro during incubation in simulated body fluid (SBF) was also studied. It was found that the rate of increased bonding strength between the cpTi implants and the host bone was the highest, whereas around the SS implants it was the slowest. At 10 days postimplant insertion, the shear strength of the cpTi implants was 2.2‐ and 4‐fold significantly higher than for the Ti‐6Al‐4V and the SS implants, respectively. Spontaneous formation of the HA globules on the cpTi and Ti‐6Al‐4V implants that were incubated in the SBF was observed as early as 6 and 10 days after incubation in SBF, respectively, whereas on SS implants, deposition of HA was evident only after 2 weeks of in vitro incubation in SBF. It is concluded that the chemical surface characteristics and the biocompatibility of the implants probably play a key role in the process of bone growth next to them, during the formation of bone in vivo. The rate of bony ingrowth to various metal implants alloys inserted into the medullar canal of rats correlates well with the induction of apatite formation on them during incubation in vitro with SBF. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009
Influence of topography of nanofibrils of three‐dimensional collagen gel beads on the phenotype, proliferation, and maturation of osteoblasts
Authors: Tsai Shiao‐Wen , Chen Chia‐Chun , Chen Pao‐Liang , Hsu Fu‐Yin 
Published: December 2008

AbstractOur objectives were to fabricate three‐dimensional collagen/chondroitin sulfate beads using mild conditions and no chemical reagents, and subsequently to investigate the influence of the nanotopography of these beads on primary osteoblast and MG63 cell responses, including cell morphology, proliferation rate, and gene expression. The major principle used to prepare beads was complex coacervation, with which we could obtain a three‐dimensional collagen matrix with or without a characteristic D‐pattern. Therefore, we utilized primary osteoblasts and MG63, an osteoblast‐like cell line, to examine the effects of specific structures on cellular behaviors. We found that the phenotype of primary osteoblasts grown on D‐periodic beads was a polygonal shape with extending lamellipodia; however, a greater number of cells displayed a circular morphology on the non‐D‐periodic carriers. After 7 and 14 days, MG63 cells on D‐periodic beads expressed higher levels of osteopontin, alkaline phosphatase activity, type I collagen, and osteocalcin than those on the non‐D‐periodic beads. Together, these data demonstrate that the unique D‐pattern of collagen not only enhances the gene expression and mineralization of osteoblasts but also induces the cells to display the normal phenotype, which indicates that the nanotopography of carriers may regulate cellular responses through the spatial control of downstream signaling. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009