bluuebunny/crossref_metadata_2025_split huggingface dataset:
MBD5 regulates iron metabolism via methylation‐independent genomic targeting of Fth1 through KAT2A in mice
Authors: Tao Yunlong , Wu Qian , Guo Xin , Zhang Zhuzhen , Shen Yuanyuan , Wang Fudi 
Published: April 2014

SummaryFerritin plays important roles in iron metabolism and controls iron absorption in the intestine. The ferritin subunits ferritin heavy chain (Fth1) and ferritin light chain (Ftl1) are tightly regulated at both the transcriptional and post‐transcriptional levels. However, mechanisms of maintaining stable, basal expression of Fth1 are poorly understood. Here, we show that global deletion of Mbd5 in mice induces an iron overload phenotype. Liver and serum iron levels in Mbd5−/− mice were 3·2‐fold and 1·5‐fold higher respectively, than wild‐type littermates; moreover, serum ferritin was increased >5‐fold in the Mbd5−/− mice. Mbd5 encodes a member of the methyl‐CpG binding domain family; however, the precise function of this gene is poorly understood. Here, we found that intestinal Fth1 mRNA levels were decreased in Mbd5−/− mice. Loss of Fth1 expression in the intestine could lead to iron over‐absorption. Furthermore, deleting Mbd5 specifically in the intestine resulted in a phenotype similar to that of conditional deletion of Fth1 mice. An Fth1 promoter‐report luciferase assay indicated that overexpression of Mbd5 enhanced Fth1 transcription in a dose‐dependent manner. Histone H4 acetylation of the Fth1 promoter was reduced in the intestine of Mbd5−/− mice and further analysis showed that histone acetyltransferase KAT2A was essential for MBD5‐induced Fth1 transcription.
Management of the acute painful crisis in sickle cell disease‐ a re‐evaluation of the use of opioids in adult patients
Authors: Telfer Paul , Bahal Nawal , Lo Alice , Challands Joanne 
Published: April 2014

SummaryManagement of the acute painful crisis (APC) of sickle cell disease (SCD) remains unsatisfactory despite advances in the understanding and management of acute pain in other clinical settings. One reason for this is an unsophisticated approach to the use of opioid analgesics for pain management. This applies to haematologists who are responsible for developing acute sickle pain management protocols for their patients, and to health care staff in the acute care setting. The objective of this article is to evaluate the evidence for use of opioids in APC management. We have highlighted the possibilities for improving management by using alternatives to morphine, and intranasal (IN) or transmucosal routes of administration for rapid onset of analgesia in the emergency department (ED). We suggest how experience gained in managing acute sickle pain in children could be extrapolated to adolescents and young adults. We have also questioned whether patients given strong opioids in the acute setting are being safely monitored and what resources are required to ensure efficacy, safety and patient satisfaction. We also identify aspects of care where there are significant differences of opinion, which require further study by randomized controlled trial.
Persistence of recipient human leucocyte antigen (HLA) antibodies and production of donor HLA antibodies following reduced intensity allogeneic haematopoietic stem cell transplantation
Authors: Fasano Ross M. , Mamcarz Ewelina , Adams Sharon , Donohue Jerussi Theresa , Sugimoto Kyoko , Tian Xin , Flegel Willy A. , Childs Richard W. 
Published: April 2014

SummaryThe effects of reduced intensity conditioning (RIC) on human leucocyte antigen (HLA)‐alloimmunization and platelet transfusion refractoriness (PTR) following allogeneic haematopoietic stem cell transplantation (Allo‐HSCT) are unknown. We studied HLA‐alloantibodies in a cohort of 16 patients (eight HLA‐alloimmunized with pre‐transplant histories of PTR and eight non‐alloimmunized controls) undergoing Allo‐HSCT using fludarabine/cyclophosphamide‐based RIC. Pre‐ and post‐transplant serum samples were analysed for HLA‐antibodies and compared to myeloid, T‐cell and bone marrow plasma cell chimaerism. Among alloimmunized patients, the duration that HLA‐antibodies persisted post‐transplant correlated strongly with pre‐transplant HLA‐antibody mean fluorescence intensity (MFI) and PRA levels (Spearman's rank correlation = 0·954 (P = 0·0048) and 0·865 (P = 0·0083) respectively). Pre‐transplant MFI >10 000 was associated with post‐transplant HLA antibody persistence >100 d (P = 0·029). HLA‐antibodies persisted ≥100 d in 3/8 patients despite recipient chimaerism being undetectable in all lympho‐haematopoietic lineages including plasma cells. Post‐transplant de‐novo HLA‐antibodies developed in three control patients with two developing PTR; the donors for two of these patients demonstrated pre‐existing HLA‐antibodies of equivalent specificity to those in the patient, confirming donor origin. These data show HLA‐antibodies may persist for prolonged periods following RIC. Further study is needed to determine the incidence of post‐transplant PTR as a consequence of donor–derived HLA alloimmunization before recommendations on donor HLA‐antibody screening can be made.
Breaking good: the inexorable rise of BTK inhibitors in the treatment of chronic lymphocytic leukaemia
Authors: Hutchinson Claire V. , Dyer Martin J. S. 
Published: April 2014

SummaryAlthough expressed in several haematological lineages and involved in multiple different signalling pathways, Bruton tyrosine kinase (BTK) plays an indispensible role in B cells in signalling from the B cell receptor (BCR) for antigen. Many B cell malignancies remain dependent on constitutive BCR signalling, making BTK a functional therapeutic target. Several BTK inhibitors (BTKi) with different kinomes and modes of action are being assessed clinically. This review documents the efficacy and toxicity of BTKi in chronic lymphocytic leukaemia (CLL). Clinically, the furthest in development is ibrutinib (trade name, Imbruvica), an irreversible BTKi, which has shown spectacular preliminary efficacy, with rapid reductions in lymph nodes accompanied by peripheral blood lymphocytosis. The lymphocytosis resolves slowly and most patients do not enter a complete remission. Nevertheless, it is possible to maintain many CLL patients, even those with adverse cytogenetic features, on drug for many months with minimal toxicities, thus potentially transforming the therapeutic paradigms for CLL. The efficacy, lack of toxicity and oral administration of BTKi will ensure their adoption in a wide range of B cell malignancies. An outstanding challenge is to incorporate BTKi with other precision medicines in a mechanism‐based manner in order to dispense with conventional chemotherapy.
Current status of antifungal resistance and its impact on clinical practice
Authors: Alcazar‐Fuoli Laura , Mellado Emilia 
Published: April 2014

SummaryMortality linked to invasive fungal diseases remains very high despite the availability of novel antifungals and new therapeutic strategies. Candida albicans and Aspergillus fumigatus account for most invasive mycosis produced by yeast or moulds, respectively. Other Candida non‐albicans are increasingly being reported and newly emerging, as well as cryptic, filamentous fungi often cause disseminated infections in immunocompromised hosts. Management of invasive fungal infections is becoming a challenge as emerging fungal pathogens generally show poor response to many antifungals. The ability of reference antifungal susceptibility testing methods to detect emerging resistance patterns, together with the molecular characterization of antifungal resistance mechanisms, are providing useful information to optimize the effectiveness of antifungal therapy. The current status of antifungal resistance epidemiology with special emphasis on the molecular resistant mechanisms that have been described in the main pathogenic fungal species are reviewed.
Whole exome sequencing to estimate alloreactivity potential between donors and recipients in stem cell transplantation
Authors: Sampson Juliana K. , Sheth Nihar U. , Koparde Vishal N. , Scalora Allison F. , Serrano Myrna G. , Lee Vladimir , Roberts Catherine H. , Jameson‐Lee Max , Ferreira‐Gonzalez Andrea , Manjili Masoud H. , Buck Gregory A. , Neale Michael C. , Toor Amir A. 
Published: April 2014

SummaryWhole exome sequencing (WES) was performed on stem cell transplant donor‐recipient (D‐R) pairs to determine the extent of potential antigenic variation at a molecular level. In a small cohort of D‐R pairs, a high frequency of sequence variation was observed between the donor and recipient exomes independent of human leucocyte antigen (HLA) matching. Nonsynonymous, nonconservative single nucleotide polymorphisms were approximately twice as frequent in HLA‐matched unrelated, compared with related D‐R pairs. When mapped to individual chromosomes, these polymorphic nucleotides were uniformly distributed across the entire exome. In conclusion, WES reveals extensive nucleotide sequence variation in the exomes of HLA‐matched donors and recipients.
Outpatient bendamustine and idarubicin for upfront therapy of elderly acute myeloid leukaemia/myelodysplastic syndrome: a phase I/II study using an innovative statistical design
Authors: Lionberger Jack M. , Pagel John M. , Sandhu Vicky K. , Xie Hu , Shadman Mazyar , Mawad Raya , Boehm Alexandra , Dean Carol , Shannon‐Dorcy Kathleen , Scott Bart L. , Deeg Hans Joachim , Becker Pamela S. , Hendrie Paul C. , Walter Roland B. , Ostronoff Fabiana , Appelbaum Frederick R. , Estey Elihu H. 
Published: April 2014

SummaryCombinations of agents may improve outcomes among elderly acute myeloid leukaemia (AML) and high‐risk myelodysplastic syndrome (MDS) patients. We performed an adaptive phase I/II trial for newly‐diagnosed AML or high‐risk MDS patients aged ≥50 years using a Bayesian approach to determine whether 1 of 3 doses of bendamustine (45, 60, 75 mg/m2 days 1–3), together with idarubicin (12 mg/m2 days 1–2), might provide a complete response (CR) rate ≥40% with <30% grade 3–4 non‐haematological toxicity. We treated 39 patients (34 AML; five MDS with >10% marrow blasts; median age 73 years). None of the three bendamustine doses in combination with idarubicin met the required CR and toxicity rates; the 75 mg/m2 dose because of excess toxicity (two of three patients) and the 60 mg/m2 dose because of low efficacy (CR rate 10/33), although no grade 3–4 non‐haematological toxicity was seen at this dose. Median survival was 7·2 months. All patients began treatment as outpatients but hospitalization was required in 90% (35/39). Although we did not find a dose of bendamustine combined with idarubicin that would provide a CR rate of >40% with acceptable toxicity, bendamustine may have activity in AML/MDS patients, suggesting its addition to other regimens may be warranted.
R‐CHOPwith iodine‐131 tositumomab consolidation for advanced stage diffuse largeB‐cell lymphoma (DLBCL):SWOG S0433
Authors: Friedberg Jonathan W. , Unger Joseph M. , Burack W. Richard , Gopal Ajay K. , Raju Robert N. , Nademanee Auayporn P. , Kaminski Mark S. , Li Hongli , Press Oliver W. , Miller Thomas P. , Fisher Richard I. 
Published: April 2014

SummaryRadiolabelled antiCD‐20 antibodies have demonstrated single agent activity in relapsed diffuse large B‐cell lymphoma (DLBCL). The S0433 clinical trial enrolled patients with newly diagnosed, advanced stage or bulky stageII, histologically confirmedDLBCL. Patients received six cycles of R‐CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles ofCHOP, then iodine‐131 tositumomab radioimmunotherapy consolidation 30–60 d after completion of chemotherapy. The primary endpoint was 2‐year progression‐free survival (PFS). Eighty‐four eligible patients were enrolled, and 56 patients completed the entire course of protocol treatment. Of the 84 patients evaluable for treatment response, 72 [86%, 95% confidence interval (CI): 76–92%] achieved a partial response (n = 21) or a confirmed (n = 41) or unconfirmed (n = 10) complete response to therapy. With a median follow‐up of 3·9 years, the 2‐yearPFSestimate is 69% and the 2‐year overall survival estimate is 77%. Rituximab levels at time of radioimmunotherapy did not correlate with toxicity or outcome. Twenty percent of patients had double hit features (MYC+;BCL2+) by immunohistochemistry, and had inferior outcome. These current results suggest that the incorporation of novel agents earlier in therapy may ultimately have greater impact inDLBCL, as early progressions, deaths and declining performance status duringCHOPchemotherapy limited the number of patients who ultimately could benefit from radioimmunotherapy consolidation.
Long‐term follow‐up and second malignancies in 487 patients with hairy cell leukaemia
Authors: Cornet Edouard , Tomowiak Cécile , Tanguy‐Schmidt Aline , Lepretre Stéphane , Dupuis Jehan , Feugier Pierre , Devidas Alain , Mariette Clara , Leblond Véronique , Thiéblemont Catherine , Validire‐Charpy Patricia , Sutton Laurent , Gyan Emmanuel , Eisenmann Jean‐Claude , Cony‐Makhoul Pascale , Ysebaert Loïc , Troussard Xavier ,   the Société Française d'Hématologie
Published: April 2014

SummaryA large, multicentre, retrospective survey of patients with hairy cell leukaemia (HCL) was conducted in France to determine the frequency of second malignancies and to analyse the long‐term effects of the established purine nucleoside analogues (PNAs), cladribine and pentostatin. The survey retrospectively reviewed the medical history of patients and their immediate family, clinical and biological presentation at the time of HCL diagnosis, treatment choice, response to treatment, time to relapse and cause of death. Data were collected for 487 patients with HCL. Of the patients included in the survey, 18% (88/487) had a familial history of cancers, 8% (41/487) presented with malignancies before HCL diagnosis and 10% (48/487) developed second malignancies after HCL was diagnosed. An excess incidence of second malignancies was observed, with a standardized incidence ratio (SIR) of 1·86 (95% confidence interval (CI): 1·34–2·51), with no significant difference between PNAs. For second haematological malignancies alone, the SIR was markedly increased at 5·32 (95% CI: 2·90–8·92). This study highlights the high frequency of cancers in HCL patients and their family members. The frequency of second malignancies is notably increased, particularly for haematological malignancies. The respective role of pentostatin and cladribine in the development of second malignancies is debatable.
A search for meaning: telling your life with learning disabilities
Authors: Horn Jaime Helena , Moss Duncan 
Published: April 2014

Accessible summaryThis article describes one woman's experience of living life with a learning disability.It gives a summary of research into this area.It describes a narrative approach.This research is important as it helps us to understand the experiences of people with learning disabilities.SummaryResearch has identified the collective experiences of oppression, stigma and isolation in the lives of people with learning disabilities. Against the backdrop of social and cultural processes that shape and limit the life experiences of people with learning disabilities, the authors are interested in how the individual develops a sense of self and identity. The aim is to further understand the subjective world of one woman with learning disabilities, drawing attention to how meaning about herself and her world has been constructed. The authors present and analyse one woman's life story, adopting a narrative and participatory research approach, with its focus on personal experience, whilst making links between the individual and social world.
Inhibition of proteasome‐mediated glucocorticoid receptor degradation restores nitric oxide bioavailability in myocardial endothelial cells in vitro
Authors: Blecharz Kinga G. , Burek Malgorzata , Bauersachs Johann , Thum Thomas , Tsikas Dimitrios , Widder Julian , Roewer Norbert , Förster Carola Y. 
Published: April 2014

Background InformationGlucocorticoids (GCs), including the synthetic GC derivate dexamethasone, are widely used as immunomodulators. One of the numerous side effects of dexamethasone therapy is hypertension arising from reduced release of the endothelium‐derived vasodilator nitric oxide (NO).ResultsHerein, we described the role of dexamethasone and its glucocorticoid receptor (GR) in the regulation of NO synthesis in vitro using the mouse myocardial microvascular endothelial cell line, MyEND. GC treatment caused a firm decrease of extracellular NO levels, whereas the expression of endothelial NO synthase (eNOS) was not affected. However, GC application induced an impairment of tetrahydrobiopterin (BH4) concentrations as well as GTP cyclohydrolase‐1 (GTPCH‐1) expression, both essential factors for NO production upstream of eNOS. Moreover, dexamethasone stimulation resulted in a substantially decreased GR gene and protein expression in MyEND cells. Importantly, inhibition of proteasome‐mediated proteolysis of the GR or overexpression of an ubiquitination‐defective GR construct improved the bioavailability of BH4 and strengthened GTPCH‐1 expression and eNOS activity.ConclusionsSummarising our results, we propose a new mechanism involved in the regulation of NO signalling by GCs in myocardial endothelial cells. We suggest that a sufficient GR protein expression plays a crucial role for the management of GC‐induced harmful adverse effects, including deregulations of vasorelaxation arising from disturbed NO biosynthesis.
Role of cues and contexts on drug‐seeking behaviour
Authors: Perry Christina J , Zbukvic Isabel , Kim Jee Hyun , Lawrence Andrew J 
Published: April 2014

Environmental stimuli are powerful mediators of craving and relapse in substance‐abuse disorders. This review examined how animal models have been used to investigate the cognitive mechanisms through which cues are able to affect drug‐seeking behaviour. We address how animal models can describe the way drug‐associated cues come to facilitate the development and persistence of drug taking, as well as how these cues are critical to the tendency to relapse that characterizes substance‐abuse disorders. Drug‐associated cues acquire properties of conditioned reinforcement, incentive motivation and discriminative control, which allow them to influence drug‐seeking behaviour. Using these models, researchers have been able to investigate the pharmacology subserving the behavioural impact of environmental stimuli, some of which we highlight. Subsequently, we examine whether the impact of drug‐associated stimuli can be attenuated via a process of extinction, and how this question is addressed in the laboratory. We discuss how preclinical research has been translated into behavioural therapies targeting substance abuse, as well as highlight potential developments to therapies that might produce more enduring changes in behaviour.Linked ArticlesThis article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2014.171.issue‐20
Olmesartan prevents cardiac rupture in mice with myocardial infarction by modulating growth differentiation factor 15 and p53
Authors: Chen Baihe , Lu Di , Fu Yujuan , Zhang Jingwen , Huang Xiaobo , Cao Shiping , Xu Dingli , Bin Jianping , Kitakaze Masafumi , Huang Qiaobing , Liao Yulin 
Published: April 2014

Background and PurposeCardiac rupture is a catastrophic complication that occurs after acute myocardial infarction (MI) and, at present, there are no effective pharmacological strategies for preventing this condition. Here we investigated the effect of the angiotensin II receptor blocker olmesartan (Olm) on post‐infarct cardiac rupture and its underlying mechanisms of action.Experimental ApproachC57Bl/6 mice with MI were treated with Olm, aldosterone (Aldo) or vehicle. Cultured neonatal cardiomyocytes and fibroblasts were exposed to normoxia or anoxia and treated with angiotensin II (Ang II), RNH6270 (active ingredient of Olm) or Aldo.Key ResultsThe mortality rate and incidence of cardiac rupture in MI mice during the first week in the Olm‐treated group were significantly lower than in the vehicle‐treated group. Olm or RNH6270 reduced myeloperoxidase staining in the infarcted myocardium, decreased apoptosis in cultured cardiomyocytes and fibroblasts, as assessed by Hoechst staining and TUNEL assay, attenuated the accumulation of p53 and phosphorylated p53 and cleaved caspase 3 induced by MI or Ang II, as assessed by Western blotting, and up‐regulated growth differentiation factor‐15 (GDF‐15). In cultured cardiomyocytes and fibroblasts, treatment with Ang II, Aldo or anoxia significantly down‐regulated the expression of GDF‐15.Conclusions and ImplicationsOlm prevents cardiac rupture through inhibition of apoptosis and inflammation, which is attributable to the down‐regulation of p53 activity and up‐regulation of GDF‐15. Our findings suggest that early administration of an AT1 receptor anatagonist to patients with acute MI is a potential preventive approach for cardiac rupture.
Nonsuicidal self‐injury as an affect‐regulation strategy and the moderating role of impulsivity
Authors: Di Pierro Rossella , Sarno Irene , Gallucci Marcello , Madeddu Fabio 
Published: April 2014

BackgroundNonsuicidal self‐injury (NSSI) is used to cope with negative affect states. We investigated the association between impulsivity and this affect‐regulation process.MethodAffect states associated with NSSI and impulsivity traits were evaluated in 30 Italian adolescent self‐injurers (63.3% female, mean age = 16.63, SD = 0.56).ResultsNonsuicidal self‐injury was associated with decreases in affective arousal, but impulsivity moderated other affective changes. High impulsivity was associated with increases in negative high‐arousal affects after NSSI, whereas low impulsivity was associated with increases in positive affects after NSSI.ConclusionImpulsivity traits influenced the success or failure of the NSSI affect‐regulation process.
Synthesis and Antitubercular Screening of [(2‐Chloroquinolin‐3‐yl)methyl] Thiocarbamide Derivatives
Authors: Kumar Suresh , Upmanyu Neeraj , Afzal Obaid , Bawa Sandhya 
Published: April 2014

A series of 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]thiocarbamide and 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]methylthiocarbamide derivatives was synthesized as antitubercular agent. The structure of quinolinyl amines and their thiocarbamide derivatives were established on the basis of IR, 1H and 13C‐NMR and mass spectral data. All the compounds were tested in vitro for antimycobacterial activity against Mycobacterium tuberculosis (ATCC‐25177) in Lowenstein‐Jensen medium by well diffusion method and MIC by twofold serial dilution method. Results of the antitubercular screening revealed that compounds showed moderate to good antitubercular activity. Compound having two halogens in the phenyl rings viz. 3g, 3h, 4g, and 4h exhibited MIC of 50 μg/mL. The computational parameters relevant to absorption and permeation of target compounds were also calculated and found to be well correlated with antitubercular activity.