bluuebunny/crossref_metadata_2025_split huggingface dataset:
Absence of hydroxyurea‐induced mutational effects supports higher utilisation for the treatment of sickle cell anaemia
Authors: Ware Russell E. , Dertinger Stephen D. 
Published: February 2021

SummaryHydroxyurea (hydroxycarbamide) is approved for treating both children and adults with sickle cell anaemia (SCA). Fetal haemoglobin (HbF) induction is the primary treatment response, along with improved anaemia, reduced haemolysis, myelosuppression and decreased endothelial inflammation. Hydroxyurea has proven clinical efficacy for SCA — treatment significantly reduces disease manifestations and prolongs survival. Despite these recognised benefits, long‐standing concerns regarding the risks of mutagenic and potentially carcinogenic drug exposure have hampered efforts for broad hydroxyurea use in SCA, although these are based largely on outdated experimental models and treatment experiences with myeloproliferative neoplasms. Consequently, many patients with SCA are not receiving this highly effective disease‐modifying therapy. In this review, we describe the concept of genotoxicity and its laboratory measurements, summarise hydroxyurea‐associated data from both preclinical and clinical studies, and discuss carcinogenic potential. The genotoxicity results clearly demonstrate that hydroxyurea does not directly bind DNA and is not mutagenic. Rather, its genotoxic effects are limited to indirect clastogenicity occurring in select cell types, and only when high dose and time thresholds are exceeded. This absence of mutagenic activity is consistent with the observed lack of any compelling carcinogenic potential. Since hydroxyurea therapy for SCA carries minimal carcinogenic risks, the current drug labelling should be modified accordingly, and prescribing practices should be broadened to allow better access and increased utilisation of this highly effective drug.
Molecular dynamics of targeting CD38 in multiple myeloma
Authors: Malavasi Fabio , Faini Angelo C. , Morandi Fabio , Castella Barbara , Incarnato Danny , Oliviero Salvatore , Horenstein Alberto L. , Massaia Massimo , van de Donk Niels W. C. J. , Richardson Paul G. 
Published: February 2021

SummaryMultiple functions of CD38 need exploring to expand clinical application of anti‐CD38 antibodies in multiple myeloma (MM). We investigated membrane dynamics of MM cells and subsequent events when CD38 is targeted by therapeutic antibodies. Human MM cells (BF01) were co‐cultured in vitro with therapeutic antibody (or control immunoglobulin G) and analysed using gene expression profiling. Microvesicles from antibody‐exposed cells were analysed for differential gene and microRNA (miRNA) expression, and for phenotypic characterisation. Exposure of BF01 cells to anti‐CD38 antibody resulted in CD38 membrane redistribution, upregulation of metabolism‐related genes and downregulation of genes involved in cell cycle processes. Microvesicles derived from antibody‐exposed cells showed increased CD73 and CD39 expression, presence of programmed death‐ligand 1 and significant up‐/down‐modulation of miRNAs. Microvesicles accumulated around immunoglobulin Fc receptor‐positive (FcR+) cells. Upon internalisation, natural killer cells displayed significantly increased expression of genes related to activation and immune response, and downregulation of genes involved in the cell cycle. Cells may use microvesicles to transmit signals distally as part of a survival strategy. Microvesicles are equipped on their surface with enzymatic machinery leading to production of tolerogenic adenosine. Further, they are internalised in FcR+ cells with significant functional modifications. These observations have relevance for improving anti‐CD38 therapeutic antibodies through targeting this mechanism and its sequelae.
Risk of new malignancies among patients with CLL treated with chemotherapy: results of a Danish population‐based study
Authors: da Cunha‐Bang Caspar , Rostgaard Klaus , Andersen Michael A. , Rotbain Emelie C. , Grønbæk Kirsten , Frederiksen Henrik , Niemann Carsten U. , Hjalgrim Henrik 
Published: February 2021

SummaryPatients with chronic lymphocytic leukaemia (CLL) have an increased risk of new malignancies. However, limited data have been published about the impact of CLL treatment on this risk. Here we followed a Danish population‐based cohort of CLL patients for risks of new malignancies. Patients in the Danish CLL registry (2008–2017) were included. Up to 50 CLL‐free matched comparators were identified. First‐line treatment was categorized into four groups; bendamustine, chlorambucil, fludarabine or other. Patients were followed from CLL diagnosis for individual types of malignancy. Adjusted hazard ratios (HR) for new malignancies and 95% confidence intervals (95% CI) were calculated. Overall, 4286 CLL patients and 214 150 controls developed 594 and 20 565 new malignancies respectively. Risk of new malignancies was increased for CLL patients. Chemotherapy treatment was registered for 1064 (25%) patients with CLL. Chemotherapy was associated with increased HR (1·51, 95% CI: 1·3–1·8) of any new malignancy. Specifically, fludarabine was associated with an increased risk of myelodysplastic syndrome (MDS) (HR 4·93, 95% CI: 1·2–19·8). Patients with CLL are at increased risk of other haematological and solid malignancies compared to the general population. Chemotherapy exposure is associated with increased risk of second malignancies and fludarabine is associated with increased risk of MDS.
Cognitive performance as a predictor of healthcare transition in sickle cell disease
Authors: Saulsberry‐Abate Anjelica C. , Partanen Marita , Porter Jerlym S. , Podila Pradeep S. B. , Hodges Jason R. , King Allison A. , Wang Winfred C. , Schreiber Jane E. , Zhao Xiwen , Kang Guolian , Jacola Lisa M. , Hankins Jane S. 
Published: February 2021

SummaryNeurocognitive deficits in sickle cell disease (SCD) may impair adult care engagement. We investigated the relationship between neurocognitive functioning and socio‐environmental factors with healthcare transition outcomes. Adolescents aged 15–18 years who had neurocognitive testing and completed a visit with an adult provider were included. Transition outcomes included transfer interval from paediatric to adult care and retention in adult care at 12 and 24 months. Eighty adolescents (59% male, 64% HbSS/HbSβ0‐thalassaemia) were included. Mean age at adult care transfer was 18·0 (±0·3) years and transfer interval was 2·0 (±2·3) months. Higher IQ (P = 0·02; PFDR = 0·05) and higher verbal comprehension (P = 0·008; PFDR = 0·024) were associated with <2 and <6 month transfer intervals respectively. Better performance on measures of attention was associated with higher adult care retention at 12 and 24 months (P = 0·009; PFDR = 0·05 and P = 0·04; PFDR = 0·12 respectively). Transfer intervals <6 months were associated with smaller households (P = 0·02; PFDR = 0·06) and households with fewer children (P = 0·02; PFDR = 0·06). Having a working parent was associated with less retention in adult care at 12 and 24 months (P = 0·01; P = 0·02 respectively). Lower IQ, verbal comprehension, attention difficulties and environmental factors may negatively impact transition outcomes. Neurocognitive function should be considered in transition planning for youth with SCD.
Automated and unbiased discrimination of ALS from control tissue at single cell resolution
Authors: Hagemann Cathleen , Tyzack Giulia E. , Taha Doaa M. , Devine Helen , Greensmith Linda , Newcombe Jia , Patani Rickie , Serio Andrea , Luisier Raphaëlle 
Published: February 2021

AbstractHistopathological analysis of tissue sections is invaluable in neurodegeneration research. However, cell‐to‐cell variation in both the presence and severity of a given phenotype is a key limitation of this approach, reducing the signal to noise ratio and leaving unresolved the potential of single‐cell scoring for a given disease attribute. Here, we tested different machine learning methods to analyse high‐content microscopy measurements of hundreds of motor neurons (MNs) from amyotrophic lateral sclerosis (ALS) post‐mortem tissue sections. Furthermore, we automated the identification of phenotypically distinct MN subpopulations in VCP‐ and SOD1‐mutant transgenic mice, revealing common morphological cellular phenotypes. Additionally we established scoring metrics to rank cells and tissue samples for both disease probability and severity. By adapting this paradigm to human post‐mortem tissue, we validated our core finding that morphological descriptors robustly discriminate ALS from control healthy tissue at single cell resolution. Determining disease presence, severity and unbiased phenotypes at single cell resolution might prove transformational in our understanding of ALS and neurodegeneration more broadly.
Ependymoma‐like tumor with mesenchymal differentiation harboring C11orf95‐NCOA1/2 or ‐RELA fusion: A hitherto unclassified tumor related to ependymoma
Authors: Tomomasa Ran , Arai Yasuhito , Kawabata‐Iwakawa Reika , Fukuoka Kohei , Nakano Yoshiko , Hama Natsuko , Nakata Satoshi , Suzuki Nozomi , Ishi Yukitomo , Tanaka Shinya , Takahashi Jun A. , Yuba Yoshiaki , Shiota Mitsutaka , Natsume Atsushi , Kurimoto Michihiro , Shiba Yoshiki , Aoki Mikiko , Nabeshima Kazuki , Enomoto Toshiyuki , Inoue Tooru , Fujimura Junya , Kondo Akihide , Yao Takashi , Okura Naoki , Hirose Takanori , Sasaki Atsushi , Nishiyama Masahiko , Ichimura Koichi , Shibata Tatsuhiro , Hirato Junko , Yokoo Hideaki , Nobusawa Sumihito 
Published: February 2021

AbstractRecurrent fusion genes involving C11orf95, C11orf95‐RELA, have been identified only in supratentorial ependymomas among primary CNS tumors. Here, we report hitherto histopathologically unclassifiable high‐grade tumors, under the tentative label of “ependymoma‐like tumors with mesenchymal differentiation (ELTMDs),” harboring C11orf95‐NCOA1/2 or ‐RELA fusion. We examined the clinicopathological and molecular features in five cases of ELTMDs. Except for one adult case (50 years old), all cases were in children ranging from 1 to 2.5 years old. All patients presented with a mass lesion in the cerebral hemisphere. Histologically, all cases demonstrated a similar histology with a mixture of components. The major components were embryonal‐appearing components forming well‐delineated tumor cell nests composed of small uniform cells with high proliferative activity, and spindle‐cell mesenchymal components with a low‐ to high‐grade sarcoma‐like appearance. The embryonal‐appearing components exhibited minimal ependymal differentiation including a characteristic EMA positivity and tubular structures, but histologically did not fit with ependymoma because they lacked perivascular pseudorosettes, a histological hallmark of ependymoma, formed well‐delineated nests, and had diffuse and strong staining for CAM5.2. Molecular analysis identified C11orf95‐NCOA1, ‐NCOA2, and ‐RELA in two, one, and two cases, respectively. t‐distributed stochastic neighbor embedding analysis of DNA methylation data from two cases with C11orf95‐NCOA1 or ‐NCOA2 and a reference set of 380 CNS tumors revealed that these two cases were clustered together and were distinct from all subgroups of ependymomas. In conclusion, although ELTMDs exhibited morphological and genetic associations with supratentorial ependymoma with C11orf95‐RELA, they cannot be regarded as ependymoma. Further analyses of more cases are needed to clarify their differences and similarities.
The formation of the Sichuan Basin, South China, during the Late Ediacaran to Early Cambrian
Authors: Gu Zhidong , Lonergan Lidia , Zhai Xiufen , Zhang Baomin , Lu Weihua 
Published: February 2021

AbstractThe Upper Ediacaran to Lower Cambrian of the Sichuan Basin in South China has long been considered to be dominated by shallow‐water deposition. Hydrocarbon exploration, however, has revealed that a NW‐SE trending intraplatform trough formed in the basin during the same period. Although different models have been proposed, the formation and evolution of the trough are still not fully understood. In this study, we investigate both the origin of the intraplatform trough and the formation of the Sichuan Basin by integrating seismic interpretation, well correlation and tectonic subsidence analysis. The seismic and well data clearly show three stages of development of the trough. The first stage, in the early Late Ediacaran, is characterized by considerable thinning of the lower two members of the Upper Ediacaran from the platform margins to the trough. In the second stage, in the late Late Ediacaran, the platform margins backstepped and the extent of the trough expanded significantly to a width of ca. ~400 km. The third stage, in the early Early Cambrian, was dominated by gradual filling of the trough and onlapping of the platform margins. Backstripped tectonic subsidence curves show one, or two closely spaced episodes of linear subsidence starting at ~550 Ma and then decreasing exponentially until ~450 Ma. The shape of the subsidence curves is consistent with formation of the Sichuan Basin by low, and slow amounts of lithospheric stretching of thickened cratonic lithosphere. The tectonic subsidence increases from the centre to the NW of the basin. Interestingly the margins of the trough do not correlate with contoured values of increased tectonic subsidence and we infer that the trough was a palaeogeographic embayment in a large carbonate platform that developed in a broad, ramp‐like area of slow and low subsidence tilting down to the proto‐Tethyan ocean located to the NW of the basin.
Prophylactic antiviral therapy for hepatitis B virus surface antigen‐positive patients with diffuse large B‐cell lymphoma treated with rituximab‐containing chemotherapy
Authors: Yamauchi Nobuhiko , Maruyama Dai , Choi Ilseung , Atsuta Yoshiko , Sakai Rika , Miyashita Kazuho , Moriuchi Yukiyoshi , Tsujimura Hideki , Kubota Nobuko , Yamamoto Go , Igarashi Tadahiko , Izutsu Koji , Yoshida Shinichiro , Kojima Kensuke , Uchida Toshiki , Inoue Yoshiko , Tsukamoto Norifumi , Ohtsuka Eiichi , Suzuki Sachiko , Inaguma Yoko , Ichikawa Satoshi , Gomyo Hiroshi , Ushijima Yoko , Nosaka Kisato , Kurata Mio , Tanaka Yasuhito , Ueda Ryuzo , Mizokami Masashi , Kusumoto Shigeru 
Published: February 2021

AbstractWe conducted a nationwide retrospective analysis of 116 hepatitis B virus (HBV) surface antigen (HBsAg)‐positive patients with diffuse large B‐cell lymphoma (DLBCL) and 278 HBsAg‐negative patients with DLBCL, as a control cohort, who received rituximab‐containing regimens as an induction chemotherapy at 30 Japanese medical centers between January 2004 and December 2014. Hepatitis was defined as an absolute serum alanine aminotransferase (ALT) level of ≥100 U/L. HBV reactivation‐related hepatitis was defined as hepatitis with an absolute serum HBV DNA level of ≥3.3 log IU/mL or an absolute increase of ≥2 log compared with the baseline value. HBsAg‐positive patients were divided into three groups based on anti–HBV prophylactic therapy: no nucleos(t)ide analogue (non–NA, n = 9), lamivudine (LAM, n = 20), and entecavir (ETV, n = 87). The 4‐year cumulative incidence (CI) of hepatitis in HBsAg‐positive and HBsAg‐negative patients was 21.1% and 14.6% (P = .081), respectively. The 4‐year CI of HBV reactivation‐related hepatitis was higher in HBsAg‐positive patients than in HBsAg‐negative patients (8.0% vs 0.4%; P < .001). Among HBsAg‐positive patients, the 4‐year CI of HBV reactivation‐related hepatitis was the highest in the non–NA group (33.3%), followed by the LAM (15.0%) and ETV (3.8%) groups (P < .001). Of note, 3 non–NA patients (33%) and 1 LAM patient (5%) (but no ETV patients) died due to HBV hepatitis. Based on Cox multivariate analysis, HBsAg positivity was not associated with poor overall survival. Prophylactic use of ETV would reduce the occurrence of HBV reactivation‐related hepatitis and mortality in HBsAg‐positive DLBCL patients receiving rituximab‐containing chemotherapy.
Revertant somatic mosaicism as a cause of cancer
Authors: Inaba Toshiya , Nagamachi Akiko 
Published: February 2021

AbstractRevertant (somatic) mosaicism is a spontaneous correction of a causative mutation in patients with congenital diseases. A relatively frequent event, revertant mosaicism may bring favorable outcomes that ameliorate disorders, and is therefore called “natural gene therapy.” However, it has been revealed recently that “overcorrection” of inherited bone marrow failure in patients with sterile alpha motif domain containing 9 (SAMD9)/9L syndromes by revertant mosaicism induces myelodysplastic syndrome (MDS) with monosomy 7 that occasionally proceeds to acute myelogenous leukemia (AML). In this review, we interpret very complex mechanisms underlying MDS/AML in patients with SAMD9/9L syndromes. This includes multiple myeloid tumor suppressors on the long arm of chromosome 7, all of which act in a haploinsufficient fashion, and a difference in sensitivity to interferon between cells carrying a mutation and revertants. Overcorrection of mutants by somatic mosaicism is likely a novel mechanism in carcinogenesis.
Does neoadjuvant FOLFOX chemotherapy improve the prognosis of high‐risk Stage II and III colon cancers? Three years' follow‐up results of the PRODIGE 22 phase II randomized multicentre trial
Authors: Karoui Mehdi , Gallois Claire , Piessen Guillaume , Legoux Jean‐Louis , Barbier Emilie , De Chaisemartin Cecile , Lecaille Cedric , Bouche Olivier , Ammarguellat Hanifa , Brunetti Francesco , Prudhomme Michel , Regimbeau Jean‐Marc , Glehen Olivier , Lievre Astrid , Portier Guillaume , Hartwig Johannes , Goujon Gael , Romain Benoit , Lepage Come , Taieb Julien ,   for PRODIGE 22 investigators/Collaborators
Published: February 2021

AbstractAimNeoadjuvant chemotherapy has proven valuable in locally advanced resectable colon cancer (CC) but its effect on oncological outcomes is uncertain. The aim of the present paper was to report 3‐year oncological outcomes, representing the secondary endpoints of the PRODIGE 22 trial.MethodPRODIGE 22 was a randomized multicentre phase II trial in high‐risk T3, T4 and/or N2 CC patients on CT scan. Patients were randomized between 6 months of adjuvant FOLFOX (upfront surgery) or perioperative FOLFOX (four cycles before surgery and eight cycles after; FOLFOX perioperative). In wild‐type RAS patients, a third arm testing perioperative FOLFOX‐cetuximab was added. The primary endpoint was the tumour regression grade. Secondary endpoints were 3‐year overall survival (OS), disease‐free survival (DFS), recurrence‐free survival (RFS) and time to recurrence (TTR).ResultsOverall, 120 patients were enrolled. At interim analysis, the FOLFOX‐cetuximab arm was stopped for futility. The remaining 104 patients represented our intention‐to‐treat population. In the perioperative group, 96% received the scheduled four neoadjuvant cycles and all but one had adjuvant FOLFOX for eight cycles. In the control arm, 38 (73%) patients received adjuvant FOLFOX. The median follow‐up was 54.3 months. Three‐year OS was 90.4% in both arms [hazard ratio (HR) = 0.85], 3‐year DFS, RFS and TTR were, respectively, 76.8% and 69.2% (HR=0.94), 73% and 69.2% (HR = 0.86) and 82% and 72% (HR = 0.67) in the perioperative and control arms, respectively. Forest plots did not show any subgroup with significant difference for survival outcomes. No benefit from adding cetuximab was observed.ConclusionPerioperative FOLFOX has no detrimental effect on long‐term oncological outcomes and may be an option for some patients with locally advanced CC.
The relationship between carotid and coronary calcification in patients with coronary artery disease
Authors: Shenouda Rafik , Vancheri Sergio , Maria Bassi Emilio , Nicoll Rachel , Sobhi Mohammed , El Sharkawy Eman , Wester Per , Vancheri Federico , Henein Michael Y. 
Published: February 2021

AbstractBackgroundAtherosclerosis is a multi‐system pathology with heterogeneous involvement.We aimed to investigate the relationship between the presence and severity of carotid and coronary calcification in a group of patients with coronary artery disease.MethodsSixty‐three patients presenting with unstable angina or positive stress test for myocardial ischaemia were enrolled in this study. All patients underwent CT scanning of the carotid and coronary arteries using the conventional protocol and Agatston scoring system. Risk factors for atherosclerosis were also analyzed for correlation with the extent of arterial calcification.ResultsTotal coronary artery calcium score (CAC) was several times higher than total carotid calcium score (1274 (1018) vs 6 (124), p = 0·0001, respectively). The left carotid calcium score correlated strongly with the right carotid calcium score (rho = 0·69, p < 0·0001). The total CAC score correlated modestly with the total carotid calcium score (rho = 0·34, p = 0·007), in particular with left carotid score (rho = 0·38, p = 0·002), but not with the right carotid score. The left coronary calcium score correlated with the right coronary calcium score (rho = 0·35, p = 0·004), left carotid calcium score (rho = 0·33, p = 0·007) and left carotid calcium score at the bifurcation (rho = 0·34, p = 0·006). While hypertension correlated with carotid calcium score, diabetes and dyslipidaemia correlated with left CAC score.ConclusionIn patients with coronary disease, the carotid calcification pattern appeared to be similar between the right and left system in contrast to that of the coronary arteries. CAC correlated only modestly with the carotid score, despite being significantly higher. Hypertension was related to carotid calcium score while diabetes and dyslipidaemia correlated with coronary calcification.
Typical angina during exercise stress testing improves the prediction of future acute coronary syndrome
Authors: Lindow Thomas , Ekström Magnus , Brudin Lars , Carlén Anna , Elmberg Viktor , Hedman Kristofer 
Published: February 2021

AbstractIntroductionThe prognostic value of angina during exercise stress testing is controversial, possibly due to previous studies not differentiating typical from non‐typical angina. We aimed to assess the prognostic value of typical angina alone, or in combination with ST depression, during exercise stress testing for predicting cardiovascular events.MethodsWe conducted a prospective observational cohort study including all patients who performed a clinical exercise stress test at the department of Clinical Physiology, Kalmar County Hospital between 2005 and 2012. The association between typical angina/ST depression and incident acute coronary syndrome (ACS) and cardiovascular mortality were analysed using Cox regression for long‐term and 1‐year follow‐up.ResultsOut of 11605 patients (median follow‐up 6.7 years), 623 (5.4%) developed ACS and 319 (2.7%) died from cardiovascular causes. Compared to patients with no angina and no ST depression, typical angina and ST depression were associated with increased risk of future ACS; hazard ratio (HR) 3.5 ([95%CI] 2.6–4.7). This association was even stronger for ACS within one year (typical angina with and without concomitant ST depression; HR 20.8 (13.9–31.3) and 9.7 (6.1–15.4), respectively). Concordance statistics for ST depression in predicting ACS during long‐term follow‐up was 0.58 (0.56–0.60) and 0.69 (0.65–0.73) for ACS within one year, and 0.64 (0.62–0.66) and 0.77 (0.73–0.81), respectively, when typical angina was added to the model.ConclusionsTypical angina during exercise stress testing is predictive of future ACS, especially in combination with ST depression, and during the first year after the test.