bluuebunny/crossref_metadata_2025_split huggingface dataset:
Essential diseases in prescribing: A national Delphi study towards a core curriculum in pharmacotherapy education
Authors: Jansen B.H.E. , Disselhorst G.W. , Schutte T. , Jansen B. , Rissmann R. , Richir M.C. , Keijsers C.J.P.W. , Vanmolkot F.H.M. , van den Brink A. Maassen , Kramers C. , Vondeling A.M. , Dumont G.J.H. , de Waard‐Siebinga I. , Van Agtmael M.A. , Tichelaar J. 
Published: August 2018

AimsPrescribing is a core skill for junior doctors, yet 8–10% of their prescriptions contain errors. To ensure adequate training in prescribing, it is important to define the diseases for which junior doctors should be competent to prescribe. The aim of the present study was therefore to identify the essential diseases in prescribing for junior doctors.MethodsA two‐round Delphi consensus study was conducted among medical specialists, general practitioners, junior doctors, pharmacists and pharmacotherapy teachers from all eight academic hospitals in the Netherlands. Using a five‐point Likert scale, the participants indicated for each item on an initial questionnaire whether it should be considered an essential disease for junior doctors. The items for which ≥80% of all respondents agreed or strongly agreed were accepted as essential diseases.ResultsSixty‐two participants completed the Delphi survey. In total, 63 of 220 items were considered to be essential diseases.ConclusionThis is the first Delphi consensus study identifying exact conditions that junior doctors must be able to prescribe for. The essential diseases can be used for training in prescribing and assessment of junior doctors' prescribing competence.
Efficacy of retreatment with immunomodulatory drugs and proteasome inhibitors following daratumumab monotherapy in relapsed and refractory multiple myeloma patients
Authors: Oostvogels Rimke , Jak Margot , Raymakers Reinier , Mous Rogier , Minnema Monique C. 
Published: August 2018

SummaryThis single‐centre retrospective observational study analysed the efficacy of retreatment with immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) after treatment with daratumumab monotherapy in patients with relapsed and/or refractory multiple myeloma (RRMM). In total 55 patients were treated with daratumumab monotherapy between 2010 and 2017. From this group 29 (53%) IMiD‐refractory patients were retreated with an IMiD after daratumumab and 6 (11%) PI‐refractory patients were retreated with a PI‐based regimen. For the IMiD‐refractory patients the overall response rate (ORR) was 52% (15/29 patients, partial response or better) upon IMiD retreatment, whereas the ORR to PI retreatment was 67% (4/6 patients) in the PI‐refractory group. The immunomodulatory effects of daratumumab may play a role in these high response rates in previously refractory patients. Due to the >6 month‐long persistence of daratumumab in the plasma the subsequent therapies can effectively be considered as combination therapy. Furthermore, the excellent tolerability of daratumumab treatment may enable patients to recover from prior lines of treatment and receive full dosing of subsequent therapies. In conclusion, a high proportion of RRMM patients benefitted from retreatment with IMiDs and PIs after daratumumab treatment. These retreatment options should therefore be explored in RRMM patients progressing on daratumumab monotherapy.
Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells
Authors: Paulus Aneel , Manna Alak , Akhtar Sharoon , Paulus Shumail M. , Sharma Mayank , Coignet Marie V. , Jiang Liuyan , Roy Vivek , Witzig Thomas E. , Ansell Stephen M. , Allan John , Furman Richard , Aulakh Sonikpreet , Manochakian Rami , Ailawadhi Sikander , Chanan‐Khan Asher A. , Sher Taimur 
Published: August 2018

SummaryCD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti‐CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells.In vitroDara treatment of WM cells (including ibrutinib‐resistant lines) elicited antibody‐dependent cellular cytotoxicity (ADCC), complement‐dependent cytotoxicity (CDC), antibody‐dependent cell phagocytosis (ADCP) and direct apoptosis.In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI‐WM1‐xenografted mice. CD38 is reported to augment B‐cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib‐resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single‐agent Dara or ibrutinib. In summary, we are the first to report thein vitroandin vivoanti‐WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co‐targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib.
Prostate artery Embolisation Assessment of Safety and feasibilitY (P‐EASY): a potential alternative to long‐term medical therapy for benign prostate hyperplasia
Authors: Brown Nicholas , Walker Duncan , McBean Rhiannon , Pokorny Morgan , Kua Boon , Gianduzzo Troy , Dunglison Nigel , Esler Rachel , Yaxley John 
Published: August 2018

ObjectivesTo assess the safety, short‐term efficacy and early functional results of prostate artery embolisation (PAE), an emerging minimally invasive treatment for symptomatic benign prostate hyperplasia (BPH).Patients and methodsIn all, 51 men with BPH (prostate size >40 mL) causing moderate–severe lower urinary tract symptoms, who had either failed or ceased medical therapy and had declined or were considered unsuitable for surgical intervention, were recruited to this study. All men underwent baseline clinical assessment, PAE, and 3‐month follow‐up. The primary endpoints of this study were safety and feasibility. Safety was measured by the incidence of post‐PAE adverse events and feasibility was defined by technical success. Secondary endpoints were changes in the International Prostate Symptom Score (IPSS) and quality of life (QoL) score at 3 months after PAE.ResultsThere were no serious adverse events and all procedures were technically successful. For non‐catheterised patients, improvement in IPSS and QoL was reported in 95.1% of cases (P < 0.001). The mean reductions in IPSS and QoL were 18.8 points (80.7%) (P < 0.001) and 3.8 points (80.6%) (P < 0.001), respectively. Of the 30 non‐indwelling‐catheter‐dependent men on medical therapy, 23 men were able to completely cease all medications, with all but one of the remaining men reporting significant improvements in IPSS and QoL score.ConclusionPAE is a technically feasible and safe procedure, with excellent short‐term efficacy. High rates of patient satisfaction were achieved in this study, along with significant reductions in prostate symptoms and improvements in QoL. PAE may be an alternative to long‐term use of medical therapy for symptoms due to BPH.
Effects of non‐euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice
Authors: Iannotti Fabio Arturo , Pagano Ester , Moriello Aniello Schiano , Alvino Filomena Grazia , Sorrentino Nicolina Cristina , D'Orsi Luca , Gazzerro Elisabetta , Capasso Raffaele , De Leonibus Elvira , De Petrocellis Luciano , Di Marzo Vincenzo 
Published: August 2018

Background and PurposeDuchenne muscular dystrophy (DMD), caused by dystrophin deficiency, results in chronic inflammation and irreversible skeletal muscle degeneration. Moreover, the associated impairment of autophagy greatly contributes to the aggravation of muscle damage. We explored the possibility of using non‐euphoric compounds present in Cannabis sativa, cannabidiol (CBD), cannabidivarin (CBDV) and tetrahydrocannabidivarin (THCV), to reduce inflammation, restore functional autophagy and positively enhance muscle function in vivo.Experimental ApproachUsing quantitative PCR, western blots and [Ca2+]i measurements, we explored the effects of CBD and CBDV on the differentiation of both murine and human skeletal muscle cells as well as their potential interaction with TRP channels. Male dystrophic mdx mice were injected i.p. with CBD or CBDV at different stages of the disease. After treatment, locomotor tests and biochemical analyses were used to evaluate their effects on inflammation and autophagy.Key ResultsCBD and CBDV promoted the differentiation of murine C2C12 myoblast cells into myotubes by increasing [Ca2+]i mostly via TRPV1 activation, an effect that undergoes rapid desensitization. In primary satellite cells and myoblasts isolated from healthy and/or DMD donors, not only CBD and CBDV but also THCV promoted myotube formation, in this case, mostly via TRPA1 activation. In mdx mice, CBD (60 mg·kg−1) and CBDV (60 mg·kg−1) prevented the loss of locomotor activity, reduced inflammation and restored autophagy.Conclusion and ImplicationsWe provide new insights into plant cannabinoid interactions with TRP channels in skeletal muscle, highlighting a potential opportunity for novel co‐adjuvant therapies to prevent muscle degeneration in DMD patients.Linked ArticlesThis article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc
Successful treatment of established heart failure in mice with recombinant HDL (Milano)
Authors: Aboumsallem Joseph Pierre , Mishra Mudit , Amin Ruhul , Muthuramu Ilayaraja , Kempen Herman , De Geest Bart 
Published: August 2018

Background and PurposeThe pleiotropic properties of HDL may exert beneficial effects on the myocardium. The effect of recombinant HDLMilano on established heart failure was evaluated in C57BL/6 mice.Experimental ApproachMice were subjected to transverse aortic constriction (TAC) or sham operation at the age of 14 weeks. Eight weeks later, TAC and sham mice were each randomized into three different groups. Reference groups were killed at day 56 after the operation for baseline analysis. Five i.p. injections of recombinant HDLMilano (MDCO‐216), 100 mg·kg−1, or an equivalent volume of control buffer were administered with a 48 h interval starting at day 56. Endpoint analyses in the control buffer groups and in the MDCO‐216 groups were executed at day 65.Key ResultsLung weight in MDCO‐216 TAC mice was 25.3% lower than in reference TAC mice and 27.9% lower than in control buffer TAC mice and was similar in MDCO‐216 sham mice. MDCO‐216 significantly decreased interstitial fibrosis and increased relative vascularity compared to reference TAC mice and control buffer TAC mice. The peak rate of isovolumetric relaxation in MDCO‐216 TAC mice was 30.4 and 36.3% higher than in reference TAC mice and control buffer TAC mice respectively. Nitro‐oxidative stress and myocardial apoptosis were significantly reduced in MDCO‐216 TAC mice compared to control buffer TAC mice.Conclusions and ImplicationsMDCO‐216 improves diastolic function, induces regression of interstitial fibrosis and normalizes lung weight in mice with established heart failure. Recombinant HDL may emerge as a treatment modality in heart failure.
Inhibition of histone deacetylase 7 reverses concentrative nucleoside transporter 2 repression in colorectal cancer by up‐regulating histone acetylation state
Authors: Ye Chaonan , Han Kun , Lei Jinxiu , Zeng Kui , Zeng Su , Ju Haixing , Yu Lushan 
Published: August 2018

Background and PurposeThe concentrative nucleoside transporter 2 (CNT2) mediates the uptake of both natural nucleosides and nucleoside‐derived drugs. Therefore, it is important both physiologically and pharmacologically. However, CNT2 expression is significantly repressed in colorectal cancer (CRC). Here, we have elucidated the mechanism(s) underlying CNT2 repression in CRC.Experimental ApproachRepression of CNT2 in tumour samples from patients with CRC was identified using Western blot and RT‐qPCR. The histone acetylation state at the CNT2 promoter region was then evaluated with chromatin immunoprecipitation and trichostatin A (TSA) treatment. To find the key enzyme responsible for hypoacetylation at the CNT2 promoter region, siRNA knockdown and RT‐qPCR were used. Effects of combining HDAC inhibitors and cladribine were studied in HCT15 and HT29 cells.Key ResultsHistone deacetylase 7 was significantly up‐regulated in CRC, leading to histone hypoacetylation at the CNT2 promoter region, especially at sites H3K9Ac, H3K18Ac and H4Ac. This hypoacetylation condensed the chromatin structure and reduced CNT2 expression. All these effects were reversed by treatment with TSA, a histone deacetylase inhibitor. In HCT15 and HT29 cells, inhibition of histone deacetylase increased cell uptake and decreased IC50 for cladribine.Conclusions and ImplicationsHistone hypoacetylation due to increased levels of histone deacetylase 7 results in CNT2 repression in CRC tumour tissue and could lead to decreased uptake of and consequent resistance to nucleoside anti‐cancer agents. Such resistance could be overcome by combining inhibitors of histone deacetylase with the nucleoside anti‐cancer agent.
Integrated fluorescent cytology with nano‐biologics in peritoneally disseminated gastric cancer
Authors: Watanabe Megumi , Kagawa Shunsuke , Kuwada Kazuya , Hashimoto Yuuri , Shigeyasu Kunitoshi , Ishida Michihiro , Sakamoto Shuichi , Ito Atene , Kikuchi Satoru , Kuroda Shinji , Kishimoto Hiroyuki , Tomida Shuta , Yoshida Ryuichi , Tazawa Hiroshi , Urata Yasuo , Fujiwara Toshiyoshi 
Published: August 2018

Gastric cancer patients positive for peritoneal cytology are at increased risk of tumor recurrence, but although a certain proportion of cytology‐positive patients relapse rapidly with aggressive progression, others survive longer with conventional chemotherapies. This heterogeneity makes it difficult to stratify patients for more intensive therapy and poses a substantial challenge for the implementation of precision medicine. We developed a new approach to identify biologically malignant subpopulations in cytology‐positive gastric cancer patients, using a green fluorescent protein (GFP)‐expressing attenuated adenovirus in which the telomerase promoter regulates viral replication (TelomeScan, OBP‐401). The fluorescence emitted from TelomeScan‐positive cells was successfully quantified using a multi‐mode microplate reader. We then analyzed clinical peritoneal washes obtained from 68 gastric cancer patients and found that patients positive for TelomeScan had a significantly worse prognosis. In 21 cytology‐positive patients, the median survival time of those who were TelomeScan positive (235 days) was significantly shorter than that for those who were TelomeScan negative (671 days; P = 0.0062). This fluorescent virus‐guided cytology detects biologically malignant cancer cells from the peritoneal washes of gastric cancer patients and may thus be useful for both therapy stratification and precision medicine approaches based on genetic profiling of disseminated cells.
Prenatal exposure to dental amalgam and risk of symptoms of attention‐deficit and hyperactivity disorder (ADHD)
Authors: Lygre Gunvor B. , Aase Heidi , Haug Kjell , Lie Stein A. , Björkman Lars 
Published: August 2018

AbstractBackgroundADHD is multifactorial, including both genetic and environmental factors. The safety of amalgam used in dental treatment has been discussed due to its content of mercury and potential risks for negative neurodevelopmental consequences in the offspring. The aim of the study was to investigate possible associations between symptoms related to ADHD in children of three and five years of age and prenatal exposure to mercury from mothers’ amalgam fillings.MethodsData from the Norwegian Mother and Child Cohort Study (MoBa) were used. Data were collected by questionnaires sent to participating women in week 17 (Q1) and 30 (Q3) of pregnancy and when the child was three (Q6) and five years of age (Q7). Information about exposure to amalgam during pregnancy was obtained from Q3. Information about symptoms related to ADHD was obtained from Q6 and Q7. Valid data were obtained for 42 163 children at three years of age and 23 392 children at five years of age. Logistic regression models, including mothers’ age, education, body mass index, parity, smoking and alcohol consumption during pregnancy, were used to estimate the association between ADHD symptoms and prenatal exposure to amalgam fillings.ResultsNo significant associations between number of teeth with amalgam filling, amalgam fillings placed or removed during pregnancy, and symptoms related to ADHD in children of three and five years of age were found.ConclusionsIn a large, prospective cohort study, we found no indication of increased risk of ADHD‐related symptoms in children prenatally exposed to mother's amalgam fillings.
Dental caries and anthropometric measures in a sample of 5‐ to 9‐year‐old children in Dhaka, Bangladesh
Authors: Mishu Masuma Pervin , Tsakos Georgios , Heilmann Anja , Watt Richard G. 
Published: August 2018

AbstractAimThis study aimed to assess associations between dental caries and anthropometric measures among a sample of children aged 5‐9 years in Dhaka, Bangladesh.MethodsA cross‐sectional observational study was conducted among 5‐ to 9‐year‐old children in Dhaka, Bangladesh. Data were collected from children and their parents attending the Dhaka Dental College Hospital and from three nearby primary schools. The outcome measures were as follows: age and sex adjusted height‐z‐scores (HAZ), weight‐z‐scores (WAZ) and BMI‐z‐scores (BAZ). Multiple linear regressions were used to assess the associations between caries and anthropometric measures, adjusted for maternal education, family income, study setting, birth weight and childhood diseases as potential confounders.ResultsThe final sample comprised 788 children, and the overall response rate was 96.7%. The majority (73.2%) had experience of dental caries. The mean dmft + DMFT score was 2.84 (95% CI 2.64, 3.03) and 35.8% experienced dental sepsis. Dental caries and sepsis were negatively associated with HAZ, WAZ and BAZ scores. After adjustment for potential confounders, children with severe levels of caries had lower HAZ scores (coefficient: −0.40; 95% CI −0.69, −0.10), lower WAZ scores (coefficient: −0.59; 95% CI −0.94, −0.24) and lower BAZ scores (coefficient: −0.50; 95% CI −0.87, −0.13) than those who were caries free. Children with moderate levels of caries also had lower WAZ scores (coefficient: −0.43; 95% CI −0.72, −0.15) and lower BAZ scores (coefficient: −0.43; 95% CI −0.72, −0.13) than caries‐free children. Children with dental sepsis had lower HAZ (coefficient: −0.23; 95% CI −0.42, −0.03), WAZ (coefficient: −0.33; 95% CI −0.56, −0.10) and BAZ scores (coefficient: −0.29; 95% CI −0.53, −0.05) than dental sepsis‐free children.ConclusionsDental caries was associated with lower height, weight and BMI among this sample of Bangladeshi children, even after adjusting for age and sex and a number of potential confounders.
Efficacy and safety of allergen immunotherapy in patients with allergy to molds: A systematic review
Authors: Di Bona Danilo , Frisenda Flavia , Albanesi Marcello , Di Lorenzo Gabriele , Caiaffa Maria Filomena , Macchia Luigi 
Published: August 2018

AbstractBackgroundAllergen immunotherapy (AIT) with mould extracts has been performed for many years but the final demonstration of its clinical efficacy is still missing, due to the small number of studies and their inconsistent results.ObjectiveTo systematically review efficacy and safety of AIT for the treatment of respiratory allergies to moulds.DesignThe primary outcomes were safety and reduction of symptoms (Symptom Score, SS) and medication use (Medication Score, MS) in patients treated with AIT compared to controls. The strength of the evidence was graded based on the risk of bias, consistency and magnitude of effect, according to the GRADE Working Group's guide.Data sourcesMedline, Web of Science and the Cochrane Library (through September 2017) supplemented with manual searches of reference lists.Eligibility criteriaRandomized studies of intervention comparing AIT to placebo/pharmacotherapy. Studies not reporting on our outcome of interest or without a control population were excluded.ResultsNine studies (168 children, 99 adults; median sample size, 27) met the inclusion criteria. The risk of bias was moderate‐to‐high in all but one study. Low strength evidence supports the assumption that AIT is effective in reducing symptoms and medication use, with only four of nine studies reporting higher benefit of AIT vs. comparators. The highest benefit of AIT compared to pharmacotherapy/placebo was reported in studies with a longer follow‐up (SMD for MS from −3.96 to −3.97 in favour of AIT) and low risk of bias (VAS for SS: 66.3 ± 13 in AIT group; 186.6 ± 39 in comparators; P < 0.05). No difference was reported with respect to study sample size, route of administration, age of participants. Generalised adverse reactions were reported in 12.5% of participants treated with sublingual immunotherapy, and 37.2% of participants treated with subcutaneous immunotherapy.ConclusionsLow strength evidence suggests that mould AIT is efficacious for the treatment of respiratory allergies. High‐quality studies with an adequate sample size are needed.
Inhibition of H3K27me3 demethylases attenuates asthma by reversing the shift in airway smooth muscle phenotype
Authors: Yu Qijun , Yu Xiaowei , Zhao Wenxue , Zhu Manni , Wang Zhengxia , Zhang Jiaxiang , Huang Mao , Zeng Xiaoning 
Published: August 2018

SummaryBackgroundThe shift in airway smooth muscle cells (ASMCs) phenotype between proliferation and contraction during asthma has been reported recently, highlighting a role of ASMCs plasticity in the pathophysiology of asthma. As an event involved in epigenetic post‐translational modification, histone H3 lysine27 (H3K27) demethylation has attracted significant attention with respect to the epigenetic changes in diverse cells; however, little is known about its contribution to the switching of ASMCs phenotype in asthma.ObjectiveTo investigate the role of trimethylated H3K27 (H3k27me3) demethylation in ASM remodelling as well as the underling mechanism.MethodsMice were exposed five times a week to house dust mite (HDM) extract for 5 weeks. Lung function was measured following the final HDM challenge. Airway inflammation and remodelling were then assessed in lungs of individual mice. Human ASMCs were purchased from Sciencell Research Laboratories. Proliferation, synthesis, migration and contraction of ASMCs were analysed, respectively.ResultsWe observed demethylation at H3k27me3 sites in lungs harvested from mice exposed to HDM extract. Administration of a selective inhibitor of H3K27 demethylase (GSK‐J4) could ameliorate the classical hallmarks of asthma, such as airway hyperresponsiveness, airway inflammation and remodelling. We established a proliferative as well as a contractive model of human ASMCs to explore the impacts of H3K27 demethylase inhibition on ASMCs phenotype. Our results indicated that GSK‐J4 decreased ASMCs proliferation and migration elicited by PDGF through the Akt/JNK signalling; GSK‐J4 also prevented the upregulation of contractile proteins in ASMCs induced by TGF‐β through the Smad3 pathway.ConclusionsInhibition of H3K27me3 demethylation alleviated the development of asthmatic airway disease in vivo and modulated ASMCs phenotype in vitro. Collectively, our findings highlight a role of H3K27me3 demethylation in experimental asthma and ASMCs phenotype switch.