bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequent proviral integration of the human betaretrovirus in biliary epithelium of patients with autoimmune and idiopathic liver disease
Authors: Wang W. , Indik S. , Wasilenko S. T. , Faschinger A. , Carpenter E. J. , Tian Z. , Zhang Y. , Wong G. K.‐S. , Mason A. L. 
Published: December 2014

SummaryBackgroundA human betaretrovirus (HBRV) has been linked with primary biliary cirrhosis (PBC) following the detection of viral particles in biliary epithelium by electron microscopy and cloning of the betaretrovirus genome from biliary epithelium and peri‐hepatic lymph nodes. Evidence for viral infection was found in the majority of PBC patients' peri‐hepatic lymph node samples. However, less than a third of the liver samples had detectable HBRV, whereas others were unable to detect betaretrovirus infection or noted the presence of virus in the liver of patients with other diagnoses.AimsTo address the hypothesis that the betaretrovirus may be below the limits of detection in the liver, biliary epithelial cells (BEC) were investigated for the evidence of infection.MethodsLigation‐mediated PCR and next generation sequencing were used to detect proviral integrations in liver, lymph nodes and BEC isolated from liver transplant recipients. Hybridisation‐based assays were used to detect betaretroviral RNA in BEC.ResultsUnique HBRV integrations and betaretrovirus RNA were detected in the majority of biliary epithelia derived from patients with PBC, autoimmune hepatitis and cryptogenic liver disease but rarely in other liver transplant recipients with primary sclerosing cholangitis and other hepatic disorders. HBRV integrations were commonly found in PBC patients' lymph nodes but rarely in whole liver samples.ConclusionsHuman betaretrovirus infection is frequently observed at the site of disease in patients with primary biliary cirrhosis and also in biliary epithelium of patients with autoimmune hepatitis and cryptogenic liver disease.
Prenatal Screening: An Ethical Agenda for the Near Future
Authors: de Jong Antina , de Wert Guido M.W.R. 
Published: December 2014

AbstractPrenatal screening for foetal abnormalities such as Down's syndrome differs from other forms of population screening in that the usual aim of achieving health gains through treatment or prevention does not seem to apply. This type of screening leads to no other options but the choice between continuing or terminating the pregnancy and can only be morally justified if its aim is to provide meaningful options for reproductive choice to pregnant women and their partners. However, this aim should not be understood as maximizing reproductive choice per se. Only if understood as allowing prospective parents to avoid suffering related to living with (a child with) serious disorders and handicaps can prenatal screening be a publicly or collectively funded programme. The alternative of moving prenatal testing outside the healthcare system into the private sector is problematic, as it makes these tests accessible only to those who can afford to pay for it. New developments in prenatal screening will have to be assessed in terms of whether and to what extent they either contribute to or undermine the stated aim of providing meaningful options for reproductive choice. In the light of this criterion, this article discusses the introduction of the new non‐invasive prenatal test (NIPT), the tendency to widen the scope of follow‐up testing, as well as the possible future scenarios of genome‐wide screening and ‘prenatal personalised medicine’. The article ends with recommendations for further debate, research and analysis.
For Your Interest? The Ethical Acceptability of Using Non‐Invasive Prenatal Testing to Test ‘Purely for Information’
Authors: Deans Zuzana , Clarke Angus J. , Newson Ainsley J. 
Published: December 2014

AbstractNon‐invasive prenatal testing (NIPT) is an emerging form of prenatal genetic testing that provides information about the genetic constitution of a foetus without the risk of pregnancy loss as a direct result of the test procedure. As with other prenatal tests, information from NIPT can help to make a decision about termination of pregnancy, plan contingencies for birth or prepare parents to raise a child with a genetic condition. NIPT can also be used by women and couples to test purely ‘for information’. Here, no particular action is envisaged following the test; it is motivated entirely by an interest in the result. The fact that NIPT can be performed without posing a risk to the pregnancy could give rise to an increase in such requests. In this paper, we examine the ethical aspects of using NIPT ‘purely for information’, including the competing interests of the prospective parents and the future child, and the acceptability of testing for ‘frivolous’ reasons. Drawing on several clinical scenarios, we claim that arguments about testing children for genetic conditions are relevant to this debate. In addition, we raise ethical concerns over the potential for objectification of the child. We conclude that, in most cases, using NIPT to test for adult‐onset conditions, carrier status or non‐serious traits presenting in childhood would be unacceptable.
Overall survival and competing risks of death in patients with Waldenström macroglobulinaemia: an analysis of theSurveillance,Epidemiology andEndResults database
Authors: Castillo Jorge J. , Olszewski Adam J. , Kanan Sandra , Meid Kirsten , Hunter Zachary R. , Treon Steven P. 
Published: December 2014

SummaryWaldenström macroglobulinaemia (WM) is a rare and incurable lymphoma. Given that the survival ofWMpatients can be prolonged, our objective was to describe trends in overall survival (OS) and analyse competing risks of death in patients withWM. The analysis included 5784 patients diagnosed withWMbetween 1991 and 2010 from theSurveillance,Epidemiology andEndResults (SEER) database. Multivariate hazard models forOSand cumulative incidence of death were fitted according to epoch of diagnosis (1991–2000 vs. 2001–10) while adjusting for age, sex, race, histology, site of involvement and registry. MedianOSfor the 1991–2000 and the 2001–10 cohorts was 6 and 8 years, respectively (P < 0·001). In the multivariate analysis, betterOS[hazard ratio (HR) 0·73, 95% confidence interval (CI) 0·67–0·79;P < 0·001] was seen in the 2001–10 cohort. Survival benefits were identified, for the 2001–10 cohort, in almost every stratum analysed, with the exception of patients aged <50 years and blacks. In the multivariate competing‐risk analysis, the 2001–10 cohort experienced lower rates ofWM‐related (HR0·57, 95%CI0·49–0·66;P < 0·001) and non‐WM‐related deaths (HR0·72, 95%CI0·66–0·79;P < 0·001). In conclusion, there have been significant improvements inOS,WM‐related and non‐WM‐related mortality in patients withWMdiagnosed in the last decade.
Use of eltrombopag after romiplostim in primary immune thrombocytopenia
Authors: González‐Porras José Ramón , Mingot‐Castellano María Eva , Andrade Marcio M. , Alonso Rafael , Caparrós Isabel , Arratibel María Carmen , Fernández‐Fuertes Fernando , Cortti Maria José , Pascual Cristina , Sánchez‐González Blanca , Bernat Silvia , Fuertes‐Palacio Miguel Angel , Vázquez‐Paganini Juan Andrés , Olivera Pavel E. , Alvarez‐Román María Teresa , Jarque Isidro , Cortés Montserrat , Martínez‐Robles Violeta , Díaz‐Gálvez Francisco Javier , Calbacho María , Fernández‐Miñano Carmen , Garcia‐Frade Javier , González‐López Tomás José 
Published: December 2014

SummaryThe thrombopoietin receptor agonists (THPO‐RAs), romiplostim and eltrombopag, are effective and safe in immune thrombocytopenia (ITP). However, the value of their sequential use when no response is achieved or when adverse events occur with one THPO‐RA has not been clearly established. Here we retrospectively evaluated 51 primary ITP adult patients treated with romiplostim followed by eltrombopag. The median age of our cohort was 49 (range, 18–83) years. There were 32 women and 19 men. The median duration of romiplostim use before switching to eltrombopag was 12 (interquartile range 5–21) months. The reasons for switching were: lack of efficacy (n = 25), patient preference (n = 16), platelet‐count fluctuation (n = 6) and side‐effects (n = 4). The response rate to eltrombopag was 80% (41/51), including 67% (n = 35) complete responses. After a median follow‐up of 14 months, 31 patients maintained their response. Efficacy was maintained after switching in all patients in the patient preference, platelet‐count fluctuation and side‐effect groups. 33% of patients experienced one or more adverse events during treatment with eltrombopag. We consider the use of eltrombopag after romiplostim for treating ITP to be effective and safe. Response to eltrombopag was related to the cause of romiplostim discontinuation.
Long‐term follow‐up of dose‐adjusted EPOCH plus rituximab (DA‐EPOCH‐R) in untreated patients with poor prognosis large B‐cell lymphoma. A phase II study conducted by the Spanish PETHEMA Group
Authors: Purroy Noelia , Bergua Juan , Gallur Laura , Prieto Julio , Lopez Luis A. , Sancho Juan M. , García‐Marco Jose A. , Castellví Josep , Montes‐Moreno Santiago , Batlle Ana , de Villambrosia Sonia Gonzalez , Carnicero Fernando , Ferrando‐Lamana Lucía , Piris Miguel A , Lopez Andrés 
Published: December 2014

SummaryThis prospective multi‐institutional phase II study was designed to assess the efficacy and safety of dose‐adjustedEPOCH(etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) plus rituximab (DA‐EPOCH‐R) in untreated patients with poor prognosis large B‐cell lymphomas. Eighty‐one patients diagnosed with diffuse large B‐cell lymphoma (DLBCL,n = 68), primary mediastinalDLBCL(n = 6) and follicular lymphoma Grade 3b (n = 7), with an age‐adjusted International Prognostic Index >1, were eligible for analysis. Median age was 60 years (range: 21–77). Sixty‐five patients (80·2%) achieved complete response. After a median follow‐up time of 64 months, 10‐year event‐free survival and overall survival (OS) were 47·8% and 63·6%, respectively. None of the studied clinical and biological characteristics were associated with poorer outcome. Interestingly, patients withBCL6rearrangement achieved a 10‐yearOSof 100%, while patients withBCL2rearrangement exhibited a poorer outcome compared to activated B‐cell tumours and germinal centre B‐cell withoutBCL2rearranged tumours. Results achieved withDA‐EPOCH‐Rshowed a good long‐term outcome and a tolerable toxicity profile in high‐risk large B cell lymphoma patients. Outcome was not affected by tumour cell proliferation or by cell of origin, highlighting the requirement of new biological markers for patient subclassification of high‐riskDLBCLpatients.
3,3′‐Diindolylmethane attenuates LPS‐mediated acute liver failure by regulating miRNAs to target IRAK4 and suppress Toll‐like receptor signalling
Authors: Tomar S , Nagarkatti M , Nagarkatti P S 
Published: December 2014

Background and PurposeAcute liver failure (ALF) is a severe and potentially lethal clinical syndrome. 3,3′‐Diindolylmethane (DIM) is a natural plant‐derived compound with anti‐cancer activities. Recently, DIM has also been shown to have anti‐inflammatory properties. Here, we tested the hypothesis that DIM would suppress endotoxin‐induced ALF.Experimental ApproachWe investigated the therapeutic potential of DIM in a mouse model of D‐galactosamine/Lipopolysaccharide (GalN/LPS)‐induced ALF. The efficacy of DIM treatment was assessed by survival, liver histopathology, serum levels of alanine transaminase, pro‐inflammatory cytokines and number of activated liver macrophages. Effects of DIM on the expression of two miRNAs, 106a and 20b, and their predicted target gene were measured by qRT‐PCR and Western blotting. Effects of DIM on the release of TNF‐α from RAW264.7 macrophages transfected with mimics of these miRNAs and activated by LPS was assessed by elisa.Key ResultsDIM treatment protected mice from ALF symptoms and reduced the number of activated liver macrophages. DIM increased expression of miR‐106a and miR‐20b in liver mononuclear cells and decreased expression of their predicted target gene IL‐1 receptor‐associated kinase 4 (IRAK4), involved in signalling from Toll‐like receptor 4 (TLR4). In vitro transfection of RAW264.7 cells using miRNA mimics of miR‐106a and 20b decreased expression of IRAK4 and of TNF‐α secretion, following LPS stimulation.Conclusions and ImplicationsDIM attenuated GalN/LPS‐induced ALF by regulating the expression of unique miRNAs that target key molecules in the TLR4 inflammatory pathway. DIM may represent a potential novel hepatoprotective agent.
High‐affinity σ1 protein agonist reduces clinical and pathological signs of experimental autoimmune encephalomyelitis
Authors: Oxombre B , Lee‐Chang C , Duhamel A , Toussaint M , Giroux M , Donnier‐Maréchal M , Carato P , Lefranc D , Zéphir H , Prin L , Melnyk P , Vermersch P 
Published: December 2014

Background and PurposeSelective agonists of the sigma‐1 receptor (σ1 protein) are generally reported to protect against neuronal damage and modulate oligodendrocyte differentiation. Human and rodent lymphocytes possess saturable, high‐affinity binding sites for compounds binding to the σ1 protein and potential immunomodulatory properties have been described for σ1 protein ligands. Experimental autoimmune encephalomyelitis (EAE) is recognized as a valuable model of the inflammatory aspects of multiple sclerosis (MS). Here, we have assessed the role of a σ1 protein agonist, containing the tetrahydroisoquinoline‐hydantoin structure, in EAE.Experimental ApproachEAE was induced in SJL/J female mice by active immunization with myelin proteolipid protein (PLP)139–151 peptide. The σ1 protein agonist was injected i.p. at the time of immunization (day 0). Disease severity was assessed clinically and by histopathological evaluation of the CNS. Phenotyping of B‐cell subsets and regulatory T‐cells were performed by flow cytometry in spleen and cervical lymph nodes.Key ResultsProphylactic treatment of EAE mice with the σ1 protein agonist prevented mononuclear cell accumulation and demyelination in brain and spinal cord and increased T2 B‐cells and regulatory T‐cells, resulting in an overall reduction in the clinical progression of EAE.Conclusions and ImplicationsThis σ1 protein agonist, containing the tetrahydroisoquinoline‐hydantoin structure, decreased the magnitude of inflammation in EAE. This effect was associated with increased proportions of B‐cell subsets and regulatory T‐cells with potential immunoregulatory functions. Targeting of the σ1 protein might thus provide new therapeutic opportunities in MS.
The catalytic topoisomerase II inhibitor dexrazoxane induces DNA breaks, ATF3 and the DNA damage response in cancer cells
Authors: Deng Shiwei , Yan Tiandong , Nikolova Teodora , Fuhrmann Dominik , Nemecek Andrea , Gödtel‐Armbrust Ute , Kaina Bernd , Wojnowski Leszek 
Published: December 2014

Background and PurposeThe catalytic topoisomerase II inhibitor dexrazoxane has been associated not only with improved cancer patient survival but also with secondary malignancies and reduced tumour response.Experimental ApproachWe investigated the DNA damage response and the role of the activating transcription factor 3 (ATF3) accumulation in tumour cells exposed to dexrazoxane.Key ResultsDexrazoxane exposure induced topoisomerase IIα (TOP2A)‐dependent cell death, γ‐H2AX accumulation and increased tail moment in neutral comet assays. Dexrazoxane induced DNA damage responses, shown by enhanced levels of γ‐H2AX/53BP1 foci, ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3‐related), Chk1 and Chk2 phosphorylation, and by p53 accumulation. Dexrazoxane‐induced γ‐H2AX accumulation was dependent on ATM. ATF3 protein was induced by dexrazoxane in a concentration‐ and time‐dependent manner, which was abolished in TOP2A‐depleted cells and in cells pre‐incubated with ATM inhibitor. Knockdown of ATF3 gene expression by siRNA triggered apoptosis in control cells and diminished the p53 protein level in both control and dexrazoxane ‐treated cells. This was accompanied by increased γ‐H2AX accumulation. ATF3 knockdown also delayed the repair of dexrazoxane ‐induced DNA double‐strand breaks.Conclusions and ImplicationsAs with other TOP2A poisons, dexrazoxane induced DNA double‐strand breaks followed by activation of the DNA damage response. The DNA damage‐triggered ATF3 controlled p53 accumulation and generation of double‐strand breaks and is proposed to serve as a switch between DNA damage and cell death following dexrazoxane treatment. These findings suggest a mechanistic explanation for the diverse clinical observations associated with dexrazoxane.
The Ca2+ channel inhibitor 2‐APB reverses β‐amyloid‐induced LTP deficit in hippocampus by blocking BAX and caspase‐3 hyperactivation
Authors: Hu Wei‐Yan , He Zhi‐Yong , Yang Lu‐Jun , Zhang Ming , Xing Da , Xiao Zhi‐Cheng 
Published: December 2014

Background and PurposeAt the early stage of Alzheimer's disease (AD), the accumulation of β‐amyloid (Aβ) oligomers disturbs intracellular Ca2+ homeostasis and disrupts synaptic plasticity of brain neurons. Prevention of Aβ‐induced synaptic failure remains an unsolved problem for the treatment of AD. Here, the effects of 2‐aminoethoxydiphenyl borate (2‐APB), a non‐specific, but moderately potent Ca2+ channel inhibitor, on Aβ‐induced deficit of synaptic long‐term potentiation (LTP) and the underlying molecular mechanisms were explored.Experimental ApproachWe used hippocampal slices and primary cultures of hippocampal neurons from C57BL/6 mice. Methods applied in our study included electrophysiological recording, membrane protein extraction, Western blot assay and Ca2+ imaging.Key Results2‐APB at 10 μM effectively reversed suppression by oligomeric Aβ1–42 (500 nM) of LTP in hippocampal slices. 2‐APB also restored phosphorylation and trafficking of the glutamate receptor subunit GluA1 in Aβ‐treated hippocampal slices, supporting its protective action on synaptic function. Aβ‐mediated abnormal neuronal [Ca2+]i elevation and hyperactivation of the mitochondrial apoptotic proteins BAX, caspase‐3, and glycogen synthase kinase‐3β, were blocked by 2‐APB pretreatment. Moreover, the defict in long term potentiation deficit in hippocampal slices from APPswe/PS1ΔE9 gene mutant mice was rescued by 2‐APB at 10 μM.Conclusions and ImplicationThese data demonstrate that 2‐APB is a potentially useful chemical to protect synaptic plasticity against neurotoxic effects of Aβ in AD.
Beyond Surrogacy—A Multi‐taxon Approach to Conservation Biogeography
Authors: Smith‐Patten Brenda D. , Patten Michael A. 
Published: December 2014

AbstractBiogeographic analysis of species turnover (β diversity) of plants and animals among regions often yields conflicting results, with regions of high β diversity identified for some taxonomic groups but not others. Such discordance calls into question the use of surrogate taxa to forge conservation plans. This discordance begs for a means of comparing multiple taxa across phyla in a manner that is cost‐effective, considers limitations in computer resources in certain global regions, and is understood by policy makers and land managers. As a test case for a method taking into account these considerations, we used species lists for ten organismal groups (spanning plants, vertebrates, and invertebrates) to identify regions of high β diversity using Monmonier's algorithm, a spatially explicit technique that is readily implemented and interpreted. Data were for montane (>1000 m elevation) species across the Eastern Arc of Tanzania and Kenya and surrounding areas. Our results indicate that surrogacy does not make for the most effective expenditure of conservation efforts. We also show that to use a multi‐taxon approach one need not rely on intensive surveys of areas in order to make conservation decisions, including reserve selection. Our approach also eliminates the need for complex modeling and comparisons common to many GIS‐based complementarity techniques. Additionally, a wide variety of socioeconomic, political, demographic, geological, climatological, and evolutionary factors can be incorporated into the technique to help shape conservation biogeography from a local and regional perspective. This technique can bridge the gap between conservation biogeography theory and application in tropical regions and beyond.
Pathological response of locally advanced rectal cancer to preoperative chemotherapy without pelvic irradiation
Authors: Bensignor T. , Brouquet A. , Dariane C. , Thirot‐Bidault A. , Lazure T. , Julié C. , Nordlinger B. , Penna C. , Benoist S. 
Published: December 2014

AbstractAimPathological response to chemotherapy without pelvic irradiation is not well defined in rectal cancer. This study aimed to evaluate the objective pathological response to preoperative chemotherapy without pelvic irradiation in middle or low locally advanced rectal cancer (LARC).MethodsBetween 2008 and 2013, 22 patients with middle or low LARC (T3/4 and/or N+ and circumferential resection margin < 2 mm) and synchronous metastatic disease or a contraindication to pelvic irradiation underwent rectal resection after preoperative chemotherapy. The pathological response of rectal tumour was analysed according to the Rödel tumour regression grading (TRG) system. Predictive factors of objective pathological response (TRG 2–4) were analysed.ResultsAll patients underwent rectal surgery after a median of six cycles of preoperative chemotherapy. Of these, 20 (91%) had sphincter saving surgery and an R0 resection. Twelve (55%) patients had an objective pathological response (TRG 2–4), including one complete response. Poor response (TRG 0–1) to chemotherapy was noted in 10 (45%) patients. In univariate analyses, none of the factors examined was found to be predictive of an objective pathological response to chemotherapy. At a median follow‐up of 37.2 months, none of the 22 patients experienced local recurrence. Of the 19 patients with Stage IV rectal cancer, 15 (79%) had liver surgery with curative intent.ConclusionPreoperative chemotherapy without pelvic irradiation is associated with objective pathological response and adequate local control in selected patients with LARC. Further prospective controlled studies will address the question of whether it can be used as a valuable alternative to radiochemotherapy in LARC.