bluuebunny/crossref_metadata_2025_split huggingface dataset:
An in vitro endodontic model to quantify the accessory canal filling potential of the vertical and lateral condensation techniques
Authors: Wolf Thomas Gerhard , Willems Louisa , Briseño‐Marroquín Benjamín 
Published: November 2020

AbstractThe purpose of this study was to determine the accessory canal filling potential of vertical and lateral condensation techniques in simulated root canals. A total of 130 prepared transparent, straight‐simulated root canals with nine accessory canals (0.02 mm), prepared at different levels from the apical, were obturated with vertical (n = 100) and 30 lateral condensation (n = 30) techniques. 50.33% of the accessory canals obturated with vertical condensation were completely filled with gutta‐percha; 37.78% completely filled with gutta‐percha and sealer. 61.11% of the accessory canals were completely filled with sealer only using the lateral condensation technique. The vertical condensation technique filled the accessory canals more frequently than the lateral condensation techniques. The lateral condensation technique was not capable of delivering gutta‐percha to any of the accessory canals. The apical third showed the lowest accessory canal filling frequency with both techniques.
Comparison of infection risks and clinical outcomes in patients with and without SARS‐CoV‐2 lung infection under renin–angiotensin–aldosterone system blockade: Systematic review and meta‐analysis
Authors: Chu Chang , Zeng Shufei , Hasan Ahmed A. , Hocher Carl‐Friedrich , Krämer Bernhard K. , Hocher Berthold 
Published: November 2020

AimsAngiotensin‐converting enzyme‐2 (ACE2) is the receptor for SARS‐CoV‐2. Animal studies suggest that renin–angiotensin–aldosterone system (RAAS) blockers might increase the expression of ACE2 and potentially increase the risk of SARS‐CoV‐2 infection.Methods and ResultsThe effect of ACE inhibitor (ACEI) treatment on the pneumonia incidence in non‐COVID‐19 patients (25 studies, 330 780 patients) was associated with a 26% reduction of pneumonia risk (odds ratio [OR]: 0.74, P < .001). Pneumonia‐related death cases in ACEI‐treated non‐COVID‐19 patients were reduced by 27% (OR: 0.73, P = .004). However, angiotensin II receptor blockers (ARB) treatment (10 studies, 275 621 non‐COVID‐19 patients) did not alter pneumonia risk in patients. Pneumonia‐related death cases in ARB‐treated non‐COVID‐19 patients was analysed only in 1 study and was significantly reduced (OR, 0.47; 95% confidence interval, 0.30 to 0.72). Results from 11 studies (8.4 million patients) showed that the risk of getting infected with the SARS‐CoV‐2 virus was reduced by 13% (OR: 0.87, P = .014) in patients treated with ACEI, whereas analysis from 10 studies (8.4 million patients) treated with ARBs showed no effect (OR, 0.92, P = .354). Results from 34 studies in 67 644 COVID‐19 patients showed that RAAS blockade reduces all‐cause mortality by 24% (OR = 0.76, P = .04).ConclusionACEIs reduce the risk of getting infected with the SARS‐CoV‐2 virus. Blocking the RAAS may decrease all‐cause mortality in COVID‐19 patients. ACEIs also reduce the risk of non‐COVID pneumonia. All‐cause mortality due to non‐COVID pneumonia is reduced by ACEI and potentially by ARBs.
Pembrolizumab‐induced vitiligo in a patient with lung adenocarcinoma: A case report
Authors: Bulat Vedrana , Likic Robert , Bradic Lada , Speeckaert Reinhart , Azdajic Marija Delas 
Published: November 2020

Pembrolizumab is an immune checkpoint inhibitor designed to block the interaction between programmed cell death‐1 and programmed cell death‐ligands 1 and 2. It shows efficacy in the treatment of patients with advanced nonsmall‐cell lung cancer, among others. Side effects may involve immune‐related adverse events, including vitiligo.We hereby present a 63‐year‐old Caucasian female with metastatic nonsmall‐cell lung cancer. Immunohistochemical analysis showed programmed death‐ligand 1 expression on 100% of tumour cells. The patient was eligible for immunotherapy and received pembrolizumab every 3 weeks as the first‐line treatment. Three months after initiation of immunotherapy with pembrolizumab, depigmentation appeared on her upper right thoracic area of the skin overlying the affected lung lobe. Immunotherapy was generally well tolerated. Excellent response in our subject with complete remission during 16 months of follow‐up potentially indicates that cutaneous immune‐related adverse events, such as vitiligo, might be associated with increased efficacy of pembrolizumab in metastatic lung adenocarcinoma.
Evaluation of clinical and genetic factors in the population pharmacokinetics of carbamazepine
Authors: Yip Vincent L.M. , Pertinez Henry , Meng Xiaoli , Maggs James L. , Carr Daniel F. , Park B. Kevin , Marson Anthony G. , Pirmohamed Munir 
Published: November 2020

AimsCarbamazepine can cause hypersensitivity reactions in ~10% of patients. An immunogenic effect can be produced by the electrophilic 10,11‐epoxide metabolite but not by carbamazepine. Hypothetically, certain single nucleotide polymorphisms might increase the formation of immunogenic metabolites, leading ultimately to hypersensitivity reactions. This study explores the role of clinical and genetic factors in the pharmacokinetics (PK) of carbamazepine and 3 metabolites known to be chemically reactive or formed through reactive intermediates.MethodsA combination of rich and sparse PK samples were collected from healthy volunteers and epilepsy patients. All subjects were genotyped for 20 single nucleotide polymorphisms in 11 genes known to be involved in the metabolism or transport of carbamazepine and carbamazepine 10,11‐epoxide. Nonlinear mixed effects modelling was used to build a population‐PK model.ResultsIn total, 248 observations were collected from 80 subjects. A 1‐compartment PK model with first‐order absorption and elimination best described the parent carbamazepine data, with a total clearance of 1.96 L/h, central distribution volume of 164 L and absorption rate constant of 0.45 h−1. Total daily dose and coadministration of phenytoin were significant covariates for total clearance of carbamazepine. EPHX1‐416G/G genotype was a significant covariate for the clearance of carbamazepine 10,11‐epoxide.ConclusionOur data indicate that carbamazepine clearance was affected by total dose and phenytoin coadministration, but not by genetic factors, while carbamazepine 10,11‐epoxide clearance was affected by a variant in the microsomal epoxide hydrolase gene. A much larger sample size would be required to fully evaluate the role of genetic variation in carbamazepine pharmacokinetics, and thereby predisposition to carbamazepine hypersensitivity.
Effects of CD20 antibodies and kinase inhibitors on B‐cell receptor signalling and survival of chronic lymphocytic leukaemia cells
Authors: Cavallini Chiara , Galasso Marilisa , Pozza Elisa Dalla , Chignola Roberto , Lovato Ornella , Dando Ilaria , Romanelli Maria G. , Krampera Mauro , Pizzolo Giovanni , Donadelli Massimo , Scupoli Maria T. 
Published: November 2020

SummaryRecently, clinical trial results have established inhibitors of B‐cell receptor (BCR)‐associated kinase (BAKi), with or without CD20 moniclonal antibodies (mAbs), as the preferred first‐line treatment for most chronic lymphocytic leukaemia (CLL) patients. Using phosphospecific flow cytometry, we showed that in leukaemic cells from CLL patients the CD20 therapeutic antibodies — rituximab, ofatumumab, and obinutuzumab — inhibited BCR signalling pathways targeting preferentially pBTKY551 — but not BTKY223 — and pAKT. On the contrary, ibrutinib and idelalisib reduced pBTKY223 to a higher extent than pBTKY551. The strong reduction of pAKT induced by idelalisib was enhanced by its combination with rituximab or ofatumumab. Moreover, CD20 mAbs and BAKi induced the death of leukaemia cells that was significantly potentiated by their combination. Analysis of the enhancement of cell death in these combinations revealed an approximately additive enhancement induced by rituximab or obinutuzumab combined with ibrutinib or idelalisib. Taken together, our data identified negative regulatory effects of CD20 mAbs and their combinations with BAKi on BCR signalling and cell survival in CLL. In conclusion, this study advances our understanding of mechanisms of action of CD20 mAbs as single agents or in combination with BAKi and could inform on the potential of combined therapies in ongoing and future clinical trials in patients with CLL.
Induction of therapeutic levels of HbF in genome‐edited primary β039‐thalassaemia haematopoietic stem and progenitor cells
Authors: Mingoia Maura , Caria Cristian A. , Ye Lin , Asunis Isadora , Marongiu M. Franca , Manunza Laura , Sollaino M. Carla , Wang Jiaming , Cabriolu Annalisa , Kurita Ryo , Nakamura Yukio , Cucca Francesco , Kan Yuet W. , Marini M. Giuseppina , Moi Paolo 
Published: November 2020

SummaryHereditary persistence of fetal haemoglobin (HPFH) is the major modifier of the clinical severity of β‐thalassaemia. The homozygous mutation c.‐196 C>T in the Aγ‐globin (HBG1) promoter, which causes Sardinian δβ0‐thalassaemia, is able to completely rescue the β‐major thalassaemia phenotype caused by the β039‐thalassaemia mutation, ensuring high levels of fetal haemoglobin synthesis during adulthood. Here, we describe a CRISPR/Cas9 genome‐editing approach, combined with the non‐homologous end joining (NHEJ) pathway repair, aimed at reproducing the effects of this naturally occurring HPFH mutation in both HBG promoters. After selecting the most efficient guide RNA in K562 cells, we edited the HBG promoters in human umbilical cord blood‐derived erythroid progenitor 2 cells (HUDEP‐2) and in haematopoietic stem and progenitor cells (HSPCs) from β0‐thalassaemia patients to assess the therapeutic potential of HbF induction. Our results indicate that small deletions targeting the −196‐promoter region restore high levels of fetal haemoglobin (HbF) synthesis in all cell types tested. In pools of HSPCs derived from homozygous β039‐thalassaemia patients, a 20% editing determined a parallel 20% increase of HbF compared to unedited pools. These results suggest that editing the region of HBG promoters around the −196 position has the potential to induce therapeutic levels of HbF in patients with most types of β‐thalassaemia irrespective of the β‐globin gene (HBB) mutations.
Chimeric antigen receptor (CAR) natural killer (NK)‐cell therapy: leveraging the power of innate immunity
Authors: Rafei Hind , Daher May , Rezvani Katayoun 
Published: November 2020

SummaryChimeric antigen receptor (CAR) T cells are a rapidly emerging form of cancer treatment, and have resulted in remarkable responses in refractory lymphoid malignancies. However, their widespread clinical use is limited by toxicity related to cytokine release syndrome and neurotoxicity, the logistic complexity of their manufacturing, cost and time‐to‐treatment for autologous CAR‐T cells, and the risk of graft‐versus‐host disease (GvHD) associated with allogeneic CAR‐T cells. Natural killer (NK) cells have emerged as a promising source of cells for CAR‐based therapies due to their ready availability and safety profile. NK cells are part of the innate immune system, providing the first line of defence against pathogens and cancer cells. They produce cytokines and mediate cytotoxicity without the need for prior sensitisation and have the ability to interact with, and activate other immune cells. NK cells for immunotherapy can be generated from multiple sources, such as expanded autologous or allogeneic peripheral blood, umbilical cord blood, haematopoietic stem cells, induced pluripotent stem cells, as well as cell lines. Genetic engineering of NK cells to express a CAR has shown impressive preclinical results and is currently being explored in multiple clinical trials. In the present review, we discuss both the preclinical and clinical trial progress made in the field of CAR NK‐cell therapy, and the strategies to overcome the challenges encountered.
Intravenous iron: do we adequately understand the short‐ and long‐term risks in clinical practice?
Authors: Rund Deborah 
Published: November 2020

SummaryIntravenous (IV) iron as a therapeutic agent is often administered but not always fully understood. The benefits of IV iron are well proven in many fields, particularly in nephrology. IV iron is beneficial not only for true iron deficiency but also for iron‐restricted anaemia (functional iron deficiency). Yet, the literature on intravenous iron has many inconsistencies regarding its adverse effects. Over the last several years, newer forms of iron have been developed, leading to the more regular use of iron and in larger doses. This review will summarize some of the older and newer literature regarding the differences among iron products, including the mechanisms and frequency of their adverse events (AEs). The pathway and frequency of an underrecognized adverse event (hypophosphataemia) will be discussed. Recent insights on infection risk and iron handling by macrophages are examined. Potential but presently unproven risks of iron overload due to IV iron are discussed. The impact of these on the risk:benefit ratio and dosing of intravenous iron are considered in different clinical settings, including pregnancy and cancer. IV iron is an essential component of the therapy of anaemia and understanding these issues will enable more informed treatment decisions and knowledgeable use of these drugs.
A complication risk score to evaluate clinical severity of thalassaemia syndromes
Authors: Vitrano Angela , Meloni Antonella , Addario Pollina Walter , Karimi Mehran , El‐Beshlawy Amal , Hajipour Mahmoud , Di Marco Vito , Hussain Ansari Saqib , Filosa Aldo , Ricchi Paolo , Ceci Adriana , Daar Shahina , Titi Singer Sylvia , Naserullah Zaki A. , Pepe Alessia , Scondotto Salvatore , Dardanoni Gabriella , Bonifazi Fedele , Vichinsky Elliott , Maggio Aurelio 
Published: November 2020

SummaryThe thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion‐dependent thalassaemia (TDT)], Group B [transfused non‐TDT (NTDT)] and Group C (non‐transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left‐ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients’ treatment.
Management of relapse in acute promyelocytic leukaemia treated with up‐front arsenic trioxide‐based regimens
Authors: Fouzia N. A. , Sharma Vibhor , Ganesan Saravanan , Palani Hamenth K. , Balasundaram Nithya , David Sachin , Kulkarni Uday P. , Korula Anu , Devasia Anup J. , Nair Sukesh C. , Janet Nancy Beryl , Abraham Aby , Mani Thenmozhi , Lakshmanan Jeyaseelan , Balasubramanian Poonkuzhali , George Biju , Mathews Vikram 
Published: November 2020

SummaryThe standard of care for patients with acute promyelocytic leukaemia (APL) relapsing after front‐line treatment with arsenic trioxide (ATO)‐based regimens remains to be defined. A total of 67 patients who relapsed after receiving ATO‐based up‐front therapy and were also salvaged using an ATO‐based regimen were evaluated. The median (range) age of patients was 28 (4–54) years. While 63/67 (94%) achieved a second molecular remission (MR) after salvage therapy, three (4·5%) died during salvage therapy. An autologous stem cell transplant (auto‐SCT) was offered to all patients who achieved MR, 35/63 (55·6%) opted for auto‐SCT the rest were administered an ATO + all‐trans retinoic acid maintenance regimen. The mean (SD) 5‐year Kaplan–Meier estimate of overall survival and event‐free survival of those who received auto‐SCT versus those who did not was 90·3 (5·3)% versus 58·6 (10·4)% (P = 0·004), and 87·1 (6·0)% versus 47·7 (10·3)% (P = 0·001) respectively. On multivariate analysis, failure to consolidate MR with an auto‐SCT was associated with a significantly increased risk of relapse [hazard ratio (HR) 4·91, 95% confidence interval (CI) 1·56–15·41; P = 0·006]. MR induction with ATO‐based regimens followed by an auto‐SCT in children and young adults with relapsed APL who were treated with front‐line ATO‐based regimens was associated with excellent long‐term survival.
A prognostic index for extranodal marginal‐zone lymphoma based on the mucosa‐associated lymphoid tissue International Prognostic Index and serum β2‐microglobulin levels
Authors: Kim Hyung‐Don , Cho Hyungwoo , Jeong Hyehyun , Bang Kyunghye , Kim Shin , Lee Kyoungmin , Kang Eun Hee , Park Jung Sun , Park Chan‐Sik , Huh Jooryung , Ryu Jin‐Sook , Lee Sang‐Wook , Yoon Dok Hyun , Oh Sung Yong , Suh Cheolwon 
Published: November 2020

SummaryThe mucosa‐associated lymphoid tissue (MALT) International Prognostic Index (IPI) was recently proposed as a prognostic index for patients with MALT lymphoma. We aimed to investigate the prognostic value of the serum β2‐microglobulin level in the context of MALT‐IPI, and we proposed a new prognostic index. Survival outcomes were analysed with regard to β2‐microglobulin level, MALT‐IPI, and the new prognostic index in MALT lymphoma patients (n = 571). The validity of the new prognostic index was assessed using an independent cohort (n = 216). Patients with high β2‐microglobulin levels had significantly worse progression‐free survival (PFS) and overall survival (OS) outcomes. A high β2‐microglobulin level was independently associated with poor PFS and OS. β2‐microglobulin levels further stratified patients in the MALT‐IPI intermediate‐risk group in terms of PFS and OS. A new prognostic index based on the MALT‐IPI and the β2‐microglobulin level, MALT‐IPI‐B, was proposed. The MALT‐IPI‐B was able to stratify patients into subgroups having distinct PFS and OS outcomes in both the training and validation cohorts. MALT‐IPI‐B enabled the identification of patients with poor survival outcomes who were classified into the intermediate‐risk group by the MALT‐IPI. In conclusion, this new β2‐microglobulin‐based prognostic index may have the specific advantage of identifying high‐risk patients who may require systemic treatment.
Focus on monoclonal antibodies targeting B‐cell maturation antigen (BCMA) in multiple myeloma: update 2021
Authors: Demel Ivo , Bago Julio Rodriguez , Hajek Roman , Jelinek Tomas 
Published: November 2020

AbstractRemarkable advances have been achieved in the treatment of multiple myeloma (MM) in the last decade, which saw targeted immunotherapy, represented by anti‐CD38 monoclonal antibodies, successfully incorporated across indications. However, myeloma is still considered curable in only a small subset of patients, and the majority of them eventually relapse. B‐cell maturation antigen (BCMA) is expressed exclusively in mature B lymphocytes and plasma cells, and represents an ideal new target for immunotherapy, presented by bispecific antibody (bsAb) constructs, antibody‐drug conjugates (ADCs) and chimeric antigen receptor T (CAR‐T) cells. Each of them has proved its efficacy with the potential for deep and long‐lasting responses as a single agent therapy in heavily pretreated patients. As a result, belantamab mafodotin was approved by the United States Food and Drug Administration for the treatment of relapsed/refractory MM, as the first anti‐BCMA agent. In the present review, we focus on monoclonal antibodies targeting BCMA – bsAbs and ADCs. The data from preclinical studies as well as first‐in‐human clinical trials will be reviewed, together with the coverage of their constructs and mechanisms of action. The present results have laid the groundwork for the ongoing or upcoming clinical trials with combinatory regimens, which have always been a cornerstone in the treatment of MM.
Iron accumulation in the choroid plexus, ependymal cells and CNS parenchyma in a rat strain with low‐grade haemolysis of fragile macrocytic red blood cells
Authors: Wimmer Isabella , Scharler Cornelia , Kadowaki Taro , Hillebrand Sophie , Scheiber‐Mojdehkar Barbara , Ueda Shuichi , Bradl Monika , Berger Thomas , Lassmann Hans , Hametner Simon 
Published: November 2020

AbstractIron accumulation in the CNS is associated with many neurological diseases via amplification of inflammation and neurodegeneration. However, experimental studies on iron overload are challenging, since rodents hardly accumulate brain iron in contrast to humans. Here, we studied LEWzizi rats, which present with elevated CNS iron loads, aiming to characterise choroid plexus, ependymal, CSF and CNS parenchymal iron loads in conjunction with altered blood iron parameters and, thus, signifying non‐classical entry sites for iron into the CNS. Non‐haem iron in formalin‐fixed paraffin‐embedded tissue was detected via DAB‐enhanced Turnbull Blue stainings. CSF iron levels were determined via atomic absorption spectroscopy. Ferroportin and aquaporin‐1 expression was visualised using immunohistochemistry. The analysis of red blood cell indices and serum/plasma parameters was based on automated measurements; the fragility of red blood cells was manually determined by the osmotic challenge. Compared with wild‐type animals, LEWzizi rats showed strongly increased iron accumulation in choroid plexus epithelial cells as well as in ependymal cells of the ventricle lining. Concurrently, red blood cell macrocytosis, low‐grade haemolysis and significant haemoglobin liberation from red blood cells were apparent in the peripheral blood of LEWzizi rats. Interestingly, elevated iron accumulation was also evident in kidney proximal tubules, which share similarities with the blood–CSF barrier. Our data underscore the importance of iron gateways into the CNS other than the classical route across microvessels in the CNS parenchyma. Our findings of pronounced choroid plexus iron overload in conjunction with peripheral iron overload and increased RBC fragility in LEWzizi rats may be seminal for future studies of human diseases, in which similar constellations are found.
Hybrids of aurantiamide acetate and isopropylated genipin as potential anti‐inflammatory agents: The design, synthesis, and biological evaluation
Authors: Wang Hongwei , Gao Sufan , Li Jiaming , Ma Xiaodong , Liu Wandong , Qian Shihu 
Published: November 2020

AbstractA novel series of hybrids designed on the basis of aurantiamide acetate and isopropylated genipin were synthesized and biologically evaluated as anti‐inflammatory agents. Among them, compound 7o exhibited the best inhibitory activity against TNF‐α secretion (IC50 = 16.90 μM) and was selected for further in vitro and in vivo functional study. The results demonstrated that 7o was capable of suppressing the expression of LPS‐induced iNOS and COX‐2, as well as reducing the production of NO at the concentration of 5 μM, which may be resulted from its regulation of NF‐κB signaling and MAPK signaling. Moreover, compound 7o exhibited favorable in vivo anti‐inflammatory activity with an inhibition rate of 53.32% against xylene‐induced ear swelling in mice at the dose of 5 mg/kg.