bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of ROS1 rearrangement in gastric adenocarcinoma
Authors: Lee Jeeyun , Lee Seung Eun , Kang So Young , Do In‐Gu , Lee Sujin , Ha Sang Yun , Cho Jeonghee , Kang Won Ki , Jang Jiryeon , Ou Sai‐Hong Ignatius , Kim Kyoung‐Mee 
Published: February 2013

AbstractBACKGROUND:Recently, chromosomal rearrangements involving receptor tyrosine kinases (RTKs) have been described in common epithelial malignancies, including nonsmall cell lung cancer (NSCLC), colorectal cancer, and breast cancer. One of these RTKs, c‐ros oncogene 1, receptor tyrosine kinase (ROS1), has been identified as a driver mutation in NSCLC, because its inhibition by crizotinib, an anaplastic lymphoma receptor tyrosine kinase (ALK)/met proto‐oncogene hepatocyte growth factor receptor (MET)/ROS1 inhibitor, led to significant tumor shrinkage in ROS1‐rearranged NSCLC. Currently, only human epidermal growth factor 2 (HER2)‐targeted therapy in combination with chemotherapy has been successful in significantly prolonging the survival of patients with advanced gastric cancer (GC). There is a need for the discovery of additional novel targets in GC.METHODS:Anti‐ROS1 immunohistochemistry (IHC) was used to screen 495 GC samples and was followed by simultaneous ROS1 break‐apart fluorescence in situ hybridization (FISH) and reverse transcriptase‐polymerase chain reaction (RT‐PCR) analyses in IHC‐positive samples. Fusion partners in ROS1‐rearranged GC were determined by RT‐PCR. In all 495 samples, HER2 amplification was identified with FISH, and MET expression was identified by IHC.RESULTS:Twenty‐three tumor samples were ROS1 IHC‐positive. Three of 23 patients were ROS1 FISH positive, HER2 FISH negative, and negative for MET overexpression; and 2 of those 3 patients harbored a solute carrier family 34 (sodium phosphate), member 2 (SLC34A2)‐ROS1 fusion transcripts. No fusion partner was identified in the third patient. Both patients who had SLC34A2‐ROS1 transcripts had poorly differentiated histology with recurrence and death within 2 years of curative surgery. ROS1 IHC‐positive status was not identified as an independent prognostic factor for overall survival.CONCLUSIONS:In this study, an SLC34A2‐ROS1 rearrangement was identified in GC, and the results provide a rationale for investigating the clinical efficacy of ROS1 inhibitors in this unique molecular subset of GC. Cancer 2013. © 2013 American Cancer Society.
Patterns of onset and resolution of immune‐related adverse events of special interest with ipilimumab
Authors: Weber Jeffrey S. , Dummer Reinhard , de Pril Veerle , Lebbé Celeste , Hodi F. Stephen ,   for the MDX010‐20 Investigators
Published: February 2013

AbstractBACKGROUND:Ipilimumab 3 mg/kg was the first agent to demonstrate improved survival in previously treated patients with metastatic melanoma in a phase 3 trial (MDX010‐20). Ipilimumab produced a characteristic spectrum of immune‐related adverse events (irAEs) of special interest, consistent with its immune‐based mechanism of action.METHODS:In MDX010‐20, 676 previously treated patients were randomized 3:1:1 to receive ipilimumab 3 mg/kg plus the glycoprotein 100 melanoma antigen vaccine (gp100), ipilimumab 3 mg/kg + placebo, or gp100 vaccine + placebo. For the current report, the authors conducted a detailed analysis of the time to onset and resolution of irAEs associated with ipilimumab therapy.RESULTS:Grade 2 through 5 irAEs generally developed during the induction phase of treatment (0‐12 weeks). Most, including grade 3/4 irAEs, were reversible when managed with treatment guidelines using vigilant monitoring and corticosteroids. The median time to resolution (to grade 1 or 0 or to the grade at baseline) of irAEs that had an onset during the induction phase was approximately 6 weeks for grade 2 through 4 irAEs and 8 weeks for grade 3 and 4 irAEs. Across the entire study duration, most grade 2 through 4 irAEs resolved within 12 weeks.CONCLUSIONS:Most ipilimumab‐associated irAEs, including grade 3/4 symptoms, developed within 12 weeks of initial dosing and resolved within 12 weeks of onset. IrAEs were well characterized in their evolution and could be managed using published algorithms. Cancer 2013. © 2013 American Cancer Society.
Modulation of Photophysics and pKa Shift of the Anti‐cancer Drug Camptothecin in the Nanocavities of Supramolecular Hosts
Authors: Gavvala Krishna , Sengupta Abhigyan , Hazra Partha 
Published: February 2013

AbstractThis article reports the pKa shift of an anti‐cancer drug, 20(S)‐camptothecin (CPT), upon encapsulation into the nanocavity of a cucurbit[7]uril (CB7) macrocycle. Steady‐state, time‐resolved fluorescence and electrospray ionisation mass spectrometry (ESI‐MS) studies provide evidence for the formation of both 1:1 and 2:1 (CB7⋅CPT) stoichiometries. Astonishingly, we have found that protonation of CPT takes place at a higher concentration of macrocycle (≥50 μM) when the 2:1 stoichiometric complex develops. However, we did not find any proof for protonation of CPT when it is encased by a β‐cyclodextrin cavity, which has a cavity size almost the same as that of CB7. Hence, we conclude that electron‐rich carbonyl portals of CB7 have an important role in protonation of the drug in the 2:1 inclusion complex. Docking and semi‐empirical quantum chemical calculations have been employed to gain an insight into the molecular picture of orientation of CPT in the inclusion complexes. It is clearly seen from the optimised structure of the 2:1 (CB7⋅CPT) inclusion complex that the quinoline nitrogen of CPT does not reside within either of the CB7 cavities, rather it is almost sandwiched between two CB7 rings, and therefore, it experiences huge electron density exerted by both carbonyl portals of the macrocycles. As a result, the pKa of CPT shifts from 1.2 to 6.2. Finally, controlled release of the drug has been achieved through the introduction of NaCl, which is rich in cells, as an external stimulus. We hope this recognition‐mediated binding and release mechanism can be useful for activation of the drug and controlled release of the drug in therapeutic uses.
Diabetic foot disease: impact of ulcer location on ulcer healing
Authors: Pickwell Kristy M. , Siersma Volkert D. , Kars Marleen , Holstein Per E. , Schaper Nicolaas C. ,   on behalf of the Eurodiale consortium
Published: February 2013

AbstractBackgroundHealing of heel ulcers in patients with diabetes is considered to be poor, but there is relatively little information on the influence of ulcer location on ulcer healing.MethodsThe influence of ulcer location on time to healing of diabetic foot ulcers was analysed by multivariate Cox regression analysis for 1000 patients included in the Eurodiale study, a prospective cohort study of patients with diabetic foot disease.ResultsMedian time to healing was 147 days for toe ulcers [(95% confidence interval (CI) 135–159 days)], 188 days for midfoot ulcers (95% CI 158–218 days) and 237 days for heel ulcers (95% CI 205–269 days) (p < 0.01). The median time to healing for plantar ulcers was 172 days (95% CI 157–187 days) and 155 days (95% CI 138–172 days) for nonplantar ulcers (p = 0.71). In multivariate Cox regression analysis, the hazard ratio for ulcer healing for midfoot and heel ulcers compared with toe ulcers was 0.77 (95% CI 0.64–0.92) and 0.62 (95% CI 0.47–0.83), respectively; the hazard ratio for ulcer healing for plantar versus nonplantar ulcers was 1 (95% CI 0.84–1.19). Other factors significantly influencing time to healing were the duration of diabetes, ulcer duration, the presence of heart failure and the presence of peripheral arterial disease.ConclusionsTime to ulcer healing increased progressively from toe to midfoot to heel, but did not differ between plantar and nonplantar ulcers. Our data also indicate that risk factors for longer time to healing differ from factors that affect the ultimate number of ulcers that heal (healing rate). Copyright © 2013 John Wiley & Sons, Ltd.
Preparation of a Heterodimetallic Di‐μ‐chlorido Complex of Palladium and Platinum
Authors: Sethi Navpreet K. , Whitwood Adrian C. , Bruce Duncan W. 
Published: February 2013

AbstractThe dimeric di‐μ‐chlorido anion hexachloridopalladate(II)platinate(II) has been prepared as a mixture with hexachloridodipalladate(II) and hexachloridodiplatinate(II) and has been identified by using a combination of X‐ray crystallography and 195Pt NMR spectroscopy. This is the first report of a heterodinuclear dimer of this type.
Triptycene‐Based, Carboxylate‐Bridged Biomimetic Diiron(II) Complexes
Authors: Li Yang , Soe Chan Myae Myae , Wilson Justin J. , Tuang Suan Lian , Apfel Ulf‐Peter , Lippard Stephen J. 
Published: February 2013

AbstractA triptycene‐based bis(benzimidazole) ester ligand, L3, was designed to enhance the electron‐donating ability of the heterocyclic nitrogen atoms relative to those of the first‐generation bis(benzoxazole) analogs, L1 and L2. A convergent synthesis of L3 was designed and executed. Three‐component titration experiments using UV/Vis spectroscopy revealed that the desired diiron(II) complex could be obtained with a 1:2:1 ratio of L3/Fe(OTf)2(MeCN)2/external carboxylate reactants. X‐ray crystallographic studies of two diiron complexes derived in this manner from L3 revealed their formulas to be [Fe2L3(μ‐OH)(μ‐O2CR)(OTf)2], where R = 2,6‐bis(p‐tolyl)phenyl (7) or triphenylmethyl (8). The structures are similar to that of a diiron complex derived from L1, [Fe2L1(μ‐OH)(μ‐O2CArTol)(OTf)2] (9), a notable difference being that, in 7 and 8, the geometry at iron more closely resembles square‐pyramidal than trigonal‐bipyramidal. Mössbauer spectroscopic analyses of 7 and 8 indicate the presence of high‐spin diiron(II) cores. These results demonstrate the importance of substituting benzimidazole for benzoxazole for assembling biomimetic diiron complexes with syn disposition of two N‐donor ligands, as found in O2‐activating carboxylate‐bridged diiron centers in biological systems.
Recent effects of tidal and hydro‐meteorological changes on coastal plains near the mouth of the Amazon River
Authors: Guimarães José Tasso Felix , Cohen Marcelo Cancela Lisboa , França Marlon Carlos , Pessenda Luiz Carlos Ruiz , de Jesus Souza Eduardo , Nogueira Afonso César Rodrigues , Alves Ronnie 
Published: February 2013

ABSTRACTThe goal of this work was to understand the main hydrodynamic processes acting on tidal flats of the coast of Amapá near the mouth of the Amazon River, and how they change over the short term (~ 20 years). The analysis of morphological and geobotanical units was carried out by applying processing and interpretation methods to optical and synthetic aperture radar (SAR) images, combined with data on water salinity, maximum flood height, sedimentary facies data, rainfall and river discharge. The temporal analysis of morphological and geobotanical units suggests the relative stabilization of savannah, ‘várzea’ and mangrove areas during the drier period and increasing tidal amplitude between 1987 to 1997. The wetter period and decreasing tidal amplitude between 1997 to 2008 led to an increase in the area of ‘várzea’ and lakes over savannah, and the expansion of mangroves mainly over the inundated field and tidal mud/mixed flats. Therefore, the decrease in rainfall index during the drier period is well‐correlated with the reduction of the Calçoene River discharge and jointly with increasing tidal amplitude favored the increase of migration rate of the mud bank and erosion profile along the littoral. It was followed by the increase of the Calçoene River discharge and jointly with decreasing tidal amplitude during the wetter period, favoring the development of mangroves on muddy substrates near the coastline. Copyright © 2013 John Wiley & Sons, Ltd.
CROSS-SPECIES CONSERVATION OF ENDOCRINE PATHWAYS: A CRITICAL ANALYSIS OF TIER 1 FISH AND RAT SCREENING ASSAYS WITH 12 MODEL CHEMICALS
Authors: Ankley Gerald T. , Gray L. Earl 
Published: February 2013

Abstract

Many structural and functional aspects of the vertebrate hypothalamic−pituitary−gonadal (HPG) axis are known to be highly conserved, but the significance of this from a toxicological perspective has received comparatively little attention. High-quality data generated through development and validation of Tier 1 tests for the U.S. Environmenal Protection Agency Endocrine Disruptor Screening Program (EDSP) offer a unique opportunity to compare responses of mammals versus fish to chemicals that may affect shared pathways within the HPG axis. The present study focuses on data generated with model chemicals that act (primarily) as estrogen receptor agonists (17α-ethynylestradiol, methoxychlor, bisphenol A), androgen receptor agonists (methyltestosterone, 17β-trenbolone), androgen receptor antagonists (flutamide, vincolozolin, p,p′-DDE), or inhibitors of different steroidogenic enzymes (ketoconazole, fadrozole, fenarimol, prochloraz). All 12 chemicals had been tested in the EDSP fish short-term (21 d) reproduction assay and in one or more of the four in vivo Tier 1 screens with rats (uterotrophic, Hershberger, male and female pubertal assays). There was a high concordance between the fish and rat assays with respect to identifying chemicals that impacted specific endocrine pathways of concern. Although most chemicals were detected as positive in both rat and fish assays, eliminating data from one class of vertebrate or the other would weaken the battery. For example, the effects of competitive inhibitors of steroid hormone synthesis were far more obvious in the fish assay, whereas the activity of androgen receptor antagonists was clearer in mammalian assays. The observations are significant both to the cross-species extrapolation of toxicity of HPG-active substances and the optimization of screening and testing frameworks for endocrine-disrupting chemicals. Environ. Toxicol. Chem. 2013;32:1084–1087. © 2013 SETAC
Tremors along the Queen Charlotte Margin triggered by large teleseismic earthquakes
Authors: Aiken Chastity , Peng Zhigang , Chao Kevin 
Published: February 2013

AbstractWe conduct a systematic search of tectonic tremors along the Queen Charlotte Margin (QCM) in western Canada triggered by distant earthquakes. We identify triggered tremor as non‐impulsive, high‐frequency signals coherent among several stations and coincident with passing surface waves. So far, the 2002 Mw7.9 Denali Fault, the 2004 Mw9.2 Sumatra, and the 2011 Mw9.1 Tohoku‐Oki earthquakes have triggered clear tremor in this region. The 2010 Mw8.8 Maule, Chile and the 2012 Mw8.6 Sumatra earthquakes may have triggered, but tremors in these two cases did not meet all of our criteria. The triggered tremors are mostly located east of the Queen Charlotte Fault in the southern portion of Haida Gwaii, near the epicenter of the 28 October 2012 Mw7.7 earthquake. Similar to the observations in other regions, the triggered tremors were initiated by the Love waves and continued during the subsequent Rayleigh waves. Tremor bursts correlate with both the particle velocity and displacement of the Love waves, indicating they are triggered at either low‐angle thrust or vertical strike‐slip faults. In addition, we find that the triggering potential for the QCM is controlled by a combination of amplitude, period, and incident angles.
Implication of the proprotein convertases in iron homeostasis: Proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin
Authors: Guillemot Johann , Canuel Maryssa , Essalmani Rachid , Prat Annik , Seidah Nabil G. 
Published: February 2013

Abstract

The first seven members of the proprotein convertase (PC) family activate protein precursors by cleavage after basic residues. While PC7 has no known specific substrates, it shows redundancy with other PCs. A genome-wide association study suggested that circulating levels of shed human transferrin receptor 1 (hTfR1) are regulated by PC7. We thus examined whether hTfR1 constitutes a specific substrate for PC7. Coexpression of hTfR1 with PCs in several cell lines indicated that PC7 is the only convertase that sheds this receptor into the medium. Site-directed mutagenesis showed that cleavage occurs at the unusual site KTECER100↓LA, in which the P1 Arg100 and P6 Lys95 are critical. Pharmacological treatments revealed that shedding of hTfR1 by PC7 requires endocytosis into acidic clathrin-coated vesicles. A PC7 chimera, in which the transmembrane domain and the cytosolic tail of PC7 were replaced by that of the convertase furin, lost its ability to cleave the receptor, demonstrating the importance of these domains in the regulation of PC7 function. Analysis of primary hepatocytes from mice lacking furin, PC5, PACE4, or PC7 revealed that hepcidin, which limits iron availability in the circulation, is specifically generated by furin and not by PC7. Finally, depletion of iron in the medium of hepatoma cell lines incubated with the iron chelator desferrioxamine resulted in PC7 down-regulation.

Conclusion:

Among the PC family members, only furin activates hepcidin in hepatocytes, and uniquely the full-length membrane-bound PC7 can directly shed hTfR1 by cleavage at Arg100↓. Our results support the notion that, when iron is limiting, hTfR1 levels increase at least in part by way of the down-regulation of PC7 expression.
Dietary fructose in nonalcoholic fatty liver disease
Authors: Vos Miriam B. , Lavine Joel E. 
Published: February 2013

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in adults and children. A number of genetic and environmental factors are known to predispose individuals to NAFLD. Certain dietary sugars, particularly fructose, are suspected to contribute to the development of NAFLD and its progression. The increasing quantity of fructose in the diet comes from sugar additives (most commonly sucrose and high fructose corn syrup) in beverages and processed foods. Substantial links have been demonstrated between increased fructose consumption and obesity, dyslipidemia, and insulin resistance. Growing evidence suggests that fructose contributes to the development and severity of NAFLD. In human studies, fructose is associated with increasing hepatic fat, inflammation, and possibly fibrosis. Whether fructose alone can cause NAFLD or if it serves only as a contributor when consumed excessively in the setting of insulin resistance, positive energy balance, and sedentary lifestyle is unknown. Sufficient evidence exists to support clinical recommendations that fructose intake be limited through decreasing foods and drinks high in added (fructose-containing) sugars.
Postoperative peg-interferon plus ribavirin is associated with reduced recurrence of hepatitis C virus-related hepatocellular carcinoma
Authors: Hsu Yao-Chun , Ho Hsiu J. , Wu Ming-Shiang , Lin Jaw-Town , Wu Chun-Ying 
Published: February 2013

Abstract

Hepatocellular carcinoma (HCC) frequently recurs after surgical resection. This population-based research aimed to investigate the association between postoperative antiviral treatment and risk of recurrent HCC in patients with hepatitis C virus (HCV) infection. By analyzing the Taiwan National Health Insurance Research Database, we initially screened a total of 100,938 patients diagnosed with HCC for the first time between October 2003 and December 2010. Among 2,237 antiviral-naïve HCV-infected patients with curatively resected HCC, there were 213 patients receiving antiviral treatment with pegylated interferon plus ribavirin for 16 weeks or more after surgery (treated cohort). These treated patients were matched 1:4 with 852 controls who were never treated for HCV infection (untreated cohort) by age, gender, cirrhosis, and the elapsed time between surgery and antiviral therapy. Cumulative incidences of and hazard ratios for recurrent HCC were calculated after adjusting for competing mortality. The recurrence rate of HCC was significantly lower in the treated than untreated cohort, with 52.1% (95% confidence interval [CI], 42.0-62.2%) and 63.9% (95% CI, 58.9-68.8%) after 5 years of follow-up, respectively (P = 0.001). The number needed to treat for one fewer recurrent HCC at 5 years was 8. The association between postoperative antiviral treatment and risk of recurrent HCC was independent of adjustment for multiple covariates, with an adjusted hazard ratio of 0.64 (95% CI, 0.50-0.83). Stratified analyses revealed that the attenuation in recurrence risk was greater in patients younger than 60 years and those without cirrhosis or diabetes. Conclusion: Postoperative pegylated interferon plus ribavirin is associated with reduced recurrence of HCC in patients with HCV infection. Age, liver cirrhosis, and diabetes mellitus appear to modify this association. (HEPATOLOGY 2013)
A c-Myc-MicroRNA functional feedback loop affects hepatocarcinogenesis
Authors: Han Han , Sun Dan , Li Wenjuan , Shen Hongxing , Zhu Yahui , Li Chen , Chen Yuxing , Lu Longfeng , Li Wenhua , Zhang Jinxiang , Tian Yuan , Li Youjun 
Published: February 2013

Abstract

c-Myc (Myc) plays an important role in normal liver development and tumorigenesis. We show here that Myc is pathologically activated in and essential for promoting human hepatocellular carcinoma (HCC). Myc induces HCC through a novel, microRNA (miRNA)-mediated feedback loop comprised of miR-148a-5p, miR-363-3p, and ubiquitin-specific protease 28 (USP28). Myc directly binds to conserved regions in the promoters of the two miRNAs and represses their expression. miR-148a-5p directly targets and inhibits Myc, whereas miR-363-3p destabilizes Myc by directly targeting and inhibiting USP28. Inhibition of miR-148a-5p or miR-363-3p induces hepatocellular tumorigenesis by promoting G1 to S phase progression, whereas activation of them has the opposite effects. The Myc-miRNA feedback loop is dysregulated in human HCC.

Conclusion:

These results define miR-148a-5p and miR-363-3p as negative regulators of Myc, thus revealing their heretofore unappreciated roles in hepatocarcinogenesis.
The impact of timing and prioritization on the cost-effectiveness of birth cohort testing and treatment for hepatitis C virus in the United States
Authors: McEwan Phil , Ward Thomas , Yuan Yong , Kim Ray , L'Italien Gilbert 
Published: February 2013

Abstract

Recent United States guidelines recommend one-time birth cohort testing for hepatitis C infection in persons born between 1945 and 1965; this represents a major public health policy undertaking. The purpose of this study was to assess the role of treatment timing and prioritization on predicted cost-effectiveness. The MONARCH hepatitis C lifetime simulation model was used in conjunction with a testing and treatment decision tree to estimate the cost-effectiveness of birth cohort versus risk-based testing incorporating information on age, fibrosis stage and treatment timing. The study used a 1945-1965 birth cohort and included disease progression, testing and treatment-related parameters. Scenario analysis was used to evaluate the impact of hepatitis C virus (HCV) prevalence, treatment eligibility, age, fibrosis stage and timing of treatment initiation on total costs, quality-adjusted life years (QALYs), HCV-related complications and cost-effectiveness. The cost-effectiveness of birth cohort versus risk-based testing was $28,602. Assuming 91% of the population is tested, at least 278,000 people need to be treated for birth cohort testing to maintain cost-effectiveness. Prioritizing treatment toward those with more advanced fibrosis is associated with a decrease in total cost of $7.5 billion and 59,035 fewer HCV-related complications. Total QALYs and complications avoided are maximized when treatment initiation occurs as soon as possible after testing. Conclusion: This study confirms that birth cohort testing is, on average, cost-effective. However, this remains true only when enough tested and HCV-positive subjects are treated to generate sufficient cost offsets and QALY gains. Given the practical and financial challenges associated with implementing birth cohort testing, the greatest return on investment is obtained when eligible patients are treated immediately and those with more advanced disease are prioritized. (HEPATOLOGY 2013)