bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative genomic analysis of pediatric T-cell lymphoblastic lymphoma reveals candidates of clinical significance
Authors: Khanam Tasneem , Sandmann Sarah , Seggewiss Jochen , Ruether Charlotte , Zimmermann Martin , Norvil Allison B. , Bartenhagen Christoph , Randau Gerrit , Mueller Stephanie , Herbrueggen Heidi , Hoffmann Per , Herms Stefan , Wei Lanying , Woeste Marius , Wuensch Christian , Gowher Humaira , Oschlies Ilske , Klapper Wolfram , Woessmann Wilhelm , Dugas Martin , Burkhardt Birgit 
Published: November 2020

Abstract
T-cell lymphoblastic lymphoma (T-LBL) is a heterogeneous malignancy of lymphoblasts committed to T-cell lineage. The dismal outcomes (15%-30%) after T-LBL relapse warrant establishing risk-based treatment. To our knowledge, this study presents the first comprehensive, systematic, integrated, genome-wide analysis including relapsed cases that identifies molecular markers of prognostic relevance for T-LBL. NOTCH1 was identified as the putative driver for T-LBL. An activated NOTCH/PI3K-AKT signaling axis and alterations in cell cycle regulators constitute the core oncogenic program for T-LBL. Mutated KMT2D was identified as a prognostic marker. The cumulative incidence of relapse was 47% ± 17% in patients with KMT2D mutations, compared with 14% ± 3% in wild-type KMT2D. Structural analysis of the mutated domains of KMT2D revealed a plausible impact on structure and functional consequences. These findings provide new insights into the pathogenesis of T-LBL, including high translational potential. The ongoing LBL 2018 trial (www.clinicaltrials.gov #NCT04043494) allows for prospective validation and subsequent fine tuning of the stratification criteria for T-LBL risk groups to improve survival of pediatric patients.
Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study
Authors: Klamroth Robert , Windyga Jerzy , Radulescu Vlad , Collins Peter W. , Stasyshyn Oleksandra , Ibrahim Hishamshah Mohd , Engl Werner , Tangada Srilatha D. , Savage William , Ewenstein Bruce 
Published: November 2020

Abstract
Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% has shown to be efficacious with an acceptable safety profile in people with hemophilia A (PwHA). The PROPEL trial compared safety and efficacy of 2 target FVIII troughs in PwHA aged 12 to 65 years, with severe disease, annualized bleeding rate ≥2, and previous FVIII treatment. PwHA were randomized to 12 months’ pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1% to 3% (reference arm) or 8% to 12% (elevated arm); first 6 months was treatment-adjustment period. The primary endpoint was absence of bleeds during the second 6 months, analyzed using multiple imputations (full analysis set [FAS]). In the 1% to 3% and 8% to 12% arms, respectively, point estimates (95% confidence interval) of proportions of PwHA with zero total bleeds were 42% (29% to 55%) and 62% (49% to 75%) in FAS (N = 115; P = .055) and 40% (27% to 55%) and 67% (52% to 81%) in per-protocol analysis set (N = 95; P = .015). Dosing frequency and consumption varied in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA; serious AEs in 7/115 (6%) PwHA, including 1 treatment-related in 8% to 12% arm (transient anti–FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms. No new safety signals were observed in the 8% to 12% arm. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and emphasize the importance of personalized treatment. This trial was registered at www.clinicaltrials.gov as #NCT02585960.
Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome–negative adult lymphoblastic leukemia
Authors: Ribera Josep-Maria , Morgades Mireia , Ciudad Juana , Montesinos Pau , Esteve Jordi , Genescà Eulàlia , Barba Pere , Ribera Jordi , García-Cadenas Irene , Moreno María José , Martínez-Carballeira Daniel , Torrent Anna , Martínez-Sánchez Pilar , Monsalvo Silvia , Gil Cristina , Tormo Mar , Artola María Teresa , Cervera Marta , González-Campos José , Rodríguez Carlos , Bermúdez Arancha , Novo Andrés , Soria Beatriz , Coll Rosa , Amigo María-Luz , López-Martínez Aurelio , Fernández-Martín Rosa , Serrano Josefina , Mercadal Santiago , Cladera Antònia , Giménez-Conca Alberto , Peñarrubia María-Jesús , Abella Eugènia , Vall-llovera Ferran , Hernández-Rivas Jesús-María , Garcia-Guiñon Antoni , Bergua Juan-Miguel , de Rueda Beatriz , Sánchez-Sánchez María-José , Serrano Alfons , Calbacho María , Alonso Natalia , Méndez-Sánchez Jose-Ángel , García-Boyero Raimundo , Olivares Matxalen , Barrena Susana , Zamora Lurdes , Granada Isabel , Lhermitte Ludovic , Feliu Evarist , Orfao Alberto 
Published: November 2020

Abstract
The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph− adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) &lt;0.1% after induction and &lt;0.01% after early consolidation were assigned to receive delayed consolidation and maintenance therapy up to 2 years in CR. The remaining patients were allocated to allo-HSCT. CR was attained in 315/348 patients (91%), with MRD &lt;0.1% after induction in 220/289 patients (76%). By intention-to-treat, 218 patients were assigned to chemotherapy and 106 to allo-HSCT. The 5-year (±95% confidence interval) cumulative incidence of relapse (CIR), overall survival (OS), and event-free survival probabilities for the whole series were 43% ± 7%, 49% ± 7%, and 40% ± 6%, respectively, with CIR and OS rates of 45% ± 8% and 59% ± 9% for patients assigned to chemotherapy and of 40% ± 12% and 38% ± 11% for those assigned to allo-HSCT, respectively. Our results show that avoiding allo-HSCT does not hamper the outcomes of HR Ph− adult ALL patients up to 60 years with adequate MRD response after induction and consolidation. Better postremission alternative therapies are especially needed for patients with poor MRD clearance. This trial was registered at www.clinicaltrials.gov as # NCT01540812.
Real-world experience with caplacizumab in the management of acute TTP
Authors: Dutt Tina , Shaw Rebecca J. , Stubbs Matthew , Yong Jun , Bailiff Benjamin , Cranfield Tanya , Crowley Maeve P. , Desborough Michael , Eyre Toby A. , Gooding Richard , Grainger John , Hanley John , Haughton Joanna , Hermans Joannes , Hill Quentin , Humphrey Louise , Lowe Gillian , Lyall Hamish , Mohsin Muhammad , Nicolson Phillip L. R. , Priddee Nicole , Rampotas Alexandros , Rayment Rachel , Rhodes Susan , Taylor Alice , Thomas William , Tomkins Oliver , Van Veen Joost J. , Lane Steven , Toh Cheng-Hock , Scully Marie 
Published: November 2020

Abstract
The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti–von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P &lt; .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity &lt; 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced &gt;48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.
ER-associated degradation preserves hematopoietic stem cell quiescence and self-renewal by restricting mTOR activity
Authors: Liu Lu , Inoki Ayaka , Fan Kelly , Mao Fengbiao , Shi Guojun , Jin Xi , Zhao Meiling , Ney Gina , Jones Morgan , Sun Shengyi , Dou Yali , Inoki Ken , Qi Ling , Li Qing 
Published: November 2020

Abstract
Hematopoietic stem cells (HSC) self-renew to sustain stem cell pools and differentiate to generate all types of blood cells. HSCs remain in quiescence to sustain their long-term self-renewal potential. It remains unclear whether protein quality control is required for stem cells in quiescence when RNA content, protein synthesis, and metabolic activities are profoundly reduced. Here, we report that protein quality control via endoplasmic reticulum-associated degradation (ERAD) governs the function of quiescent HSCs. The Sel1L/Hrd1 ERAD genes are enriched in the quiescent and inactive HSCs, and conditional knockout of Sel1L in hematopoietic tissues drives HSCs to hyperproliferation, which leads to complete loss of HSC self-renewal and HSC depletion. Mechanistically, ERAD deficiency via Sel1L knockout leads to activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, we identify Ras homolog enriched in brain (Rheb), an activator of mTOR, as a novel protein substrate of Sel1L/Hrd1 ERAD, which accumulates upon Sel1L deletion and HSC activation. Importantly, inhibition of mTOR, or Rheb, rescues HSC defects in Sel1L knockout mice. Protein quality control via ERAD is, therefore, a critical checkpoint that governs HSC quiescence and self-renewal by Rheb-mediated restriction of mTOR activity.
Bone marrow dendritic cell aggregates associate with systemic immune dysregulation in chronic myelomonocytic leukemia
Authors: Mangaonkar Abhishek A. , Reichard Kaaren K. , Binder Moritz , Coltro Giacomo , Lasho Terra L. , Carr Ryan M. , Chiu April , Negron Vivian , Hefazi Mehrdad , Anagnostou Theodora , Timm Michael M. , Hiebert James W. , Villasboas Jose C. , Gonsalves Wilson I. , Gangat Naseema , Shah Mithun , Alkhateeb Hassan B. , Al-Kali Aref , Elliott Michelle A. , Begna Kebede H. , Wolanskyj-Spinner Alexandra P. , Litzow Mark R. , Hogan William J. , Ansell Stephen M. , Pardanani Animesh , Tefferi Ayalew , Patnaik Mrinal M. 
Published: November 2020

Key Points
Systemic immune microenvironment signatures in CMML indicate an altered T- and natural killer cell balance. CMML bone marrow dendritic cell aggregates associate with disease progression and systemic regulatory T-cell phenotypic switch.
Health-related quality of life of patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis
Authors: Cox Ingrid A. , Borchers Arriagada Nicolas , de Graaff Barbara , Corte Tamera J. , Glaspole Ian , Lartey Stella , Walters E. Haydn , Palmer Andrew J. 
Published: November 2020

Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease presenting in persons 50 years and older. Through a comprehensive review of available studies, we aimed to assess health-related quality of life (HRQoL) of people living with IPF and the instruments used in this assessment.Searches were conducted up to May, 2020. Quality appraisal and data extraction were performed using pre-designed forms. Narrative synthesis approach was used to report results of the systematic review and a random effects model was used for the meta-analysis. A leave-one-out sensitivity analysis was performed, and a trim and fill method was used to assess publication bias.The review included 134 studies. The most used instruments to measure HRQoL were St George's Respiratory Questionnaire (SGRQ), Short Form 36 (SF36) and EuroQoL (EQ5D). Standardised mean scores (95% confidence interval) for these instruments were as follows: SGRQ total score: 44.72 (42.21–47.22); SF36 physical component score (PCS): 37.00 (34.74–39.26) SF36 mental component score (MCS): 50.18 (48.41–51.95); King's Brief Interstitial Lung Disease questionnaire total score: 58.38 (55.26–61.51); and EQ5D utility: 0.73 (0.68–0.79). Analysis of standardised means for both SGRQ and SF36 demonstrated worse scores in physical health domains as compared to mental health domains.This systematic review confirms that IPF negatively affected HRQoL, mostly impacting the physical health domains. This study also demonstrated that a diverse number of instruments are used to evaluate HRQoL. In view of this diversity, a standardised approach to measurement of HRQoL for IPF is important to ensure that comparisons made are reliable.
Different stability of miRNAs and endogenous control genes in archival specimens of papillary thyroid carcinoma
Authors: Pamedytyte Daina , Leipute Enrika , Zilaitiene Birute , Sarauskas Valdas , Dauksiene Dalia , Dauksa Albertas , Zvirbliene Aurelija 
Published: November 2020

Abstract

Background
The most popular miRNA quantitation technique is RQ-PCR with relative gene expression method that requires an endogenous control (EC) gene for data normalization. However, there are insufficient data and selection criteria on the most suitable ECs for miRNA expression studies in many cancer types including papillary thyroid carcinoma (PTC). Therefore, in this study we evaluated the impact of chosen EC and archival formalin-fixed, paraffin-embedded (FFPE) PTC tissue age on estimated target miRNA expression.

Methods
RQ-PCR was used to determine expression levels of five miRNAs (miR-146b, miR-222, miR-21, miR-221 and miR-181b) and three different endogenous controls (RNU48, let-7a, miR-16), which were used to normalize the data. In total, 400 FFPE PTC tissues were analyzed that have been stored from 1 to 15 years.

Results
The stability of commonly used ECs RNU48 and let-7a significantly differs from the stability of target miRNA in archival FFPE PTC tissues. Moreover, these differences have a great impact on miRNA expression results when FFPE tissue samples have been stored for a different period of time.

Conclusions
It is important to select an ECs not only stable in the tissue of interest but also with similar stability to target miRNA, especially when working with samples of different age.
Placental growth factor for the prognosis of women with preeclampsia (fullPIERS model extension): context matters
Authors:   for the fullPIERS Group, Ukah U. Vivian , Payne Beth A. , Hutcheon Jennifer A. , Chappell Lucy C. , Seed Paul T. , Conti-Ramsden Frances Inez , Ansermino J. Mark , Magee Laura A. , von Dadelszen Peter 
Published: November 2020

Abstract

Background
The fullPIERS risk prediction model was developed to identify which women admitted with confirmed diagnosis of preeclampsia are at highest risk of developing serious maternal complications. The model discriminates well between women who develop (vs. those who do not) adverse maternal outcomes. It has been externally validated in several populations. We assessed whether placental growth factor (PlGF), a biomarker associated with preeclampsia risk, adds incremental value to the fullPIERS model.

Methods
Using a cohort of women admitted into tertiary hospitals in well-resourced settings (the USA and Canada), between May 2010 to February 2012, we evaluated the incremental value of PlGF added to fullPIERS for prediction of adverse maternal outcomes within 48 h after admission with confirmed preeclampsia. The discriminatory performance of PlGF and the fullPIERS model were assessed in this cohort using the area under the receiver’s operating characteristic curve (AUROC) while the extended model (fullPIERS +PlGF) was assessed based on net reclassification index (NRI) and integrated discrimination improvement (IDI) performances.

Results
In a cohort of 541 women delivered shortly (< 1 week) after presentation, 8.1% experienced an adverse maternal outcome within 48 h of admission. Prediction of adverse maternal outcomes was not improved by addition of PlGF to fullPIERS (NRI: -8.7, IDI − 0.06). Discriminatory performance (AUROC) was 0.67 [95%CI: 0.59–0.75] for fullPIERS only and 0.67 [95%CI: 0.58–0.76]) for fullPIERS extended with PlGF, a performance worse than previously documented in fullPIERS external validation studies (AUROC > 0.75).

Conclusions
While fullPIERS model performance may have been affected by differences in healthcare context between this study cohort and the model development and validation cohorts, future studies are required to confirm whether PlGF adds incremental benefit to the fullPIERS model for prediction of adverse maternal outcomes in preeclampsia in settings where expectant management is practiced.
Range of abduction in patients with Legg-Calvé-Perthes disease – a nationwide register-based cohort study
Authors: El-Harbiti Ahmad , Hailer Yasmin D. 
Published: November 2020

AbstractBackgroundRange of abduction often decreases during Legg-Calvé-Perthes Disease (LCPD) disease. However, a good range of abduction is required during the course of LCPD, especially when containment surgery should be performed. This study aimed to investigate how many patients registered in the Swedish Pediatric Orthopedic Quality register (SPOQ) with LCPD had reduced range of abduction at diagnosis in relation to sex or age at diagnosis or severity of disease (lateral pillar class at the time at diagnosis), if physiotherapy (PT) was prescribed and has a beneficial impact in maintaining (or increasing) abduction and if the range of abduction at diagnosis before fragmentation stage is predictive for the lateral pillar classification at fragmentation stage.MethodsThe national Swedish Pediatric Orthopedic Quality Register (SPOQ), established in 2015, is used to identify patients with LCPD. The patients are registered at three time points: at diagnosis, at potential surgery and 2 years after diagnosis. Range of abduction and information on PT are required to register at all registration sessions. One hundred ninety-nine hips from 192 children were registered in the SPOQ.ResultsOf all hips, the mean range of abduction at diagnosis was 39 degrees (range 0 to 90). One hundred twenty-six patients (63%) either received instructions for PT or were referred to a physiotherapist; two patients were treated additionally with an abduction brace. There was a trend that patients who received PT, compared to patients without PT, either maintained or increased their range of abduction at the 2-year follow-up. Older age at diagnosis correlated with decreased range of abduction at the 2-year follow-up (Estimate [Est]: − 3.1, 95% confidence interval [CI]: − 4.4 to − 1.7). The degree of abduction at diagnosis before fragmentation stage correlated with the lateral pillar group at the fragmentation stage (Est: -5.3, 95% CI: − 10.0 to − 1.1).ConclusionIn all, 63% of the children with LCPD in SPOQ received either written instructions or were referred to PT or both. PT seems to have a favorable impact for maintaining the range of abduction in children with LCPD. Children with a lower range of abduction at diagnosis (before the fragmentation stage) developed a higher degree of lateral pillar involvement as measured by the lateral pillar classification.
A prospective study of the muscle strength and reaction time of the quadriceps, hamstring, and gastrocnemius muscles in patients with plantar fasciitis
Authors: Lee Jin Hyuck , Jung Hae Woon , Jang Woo Young 
Published: November 2020

Abstract

Background
Muscle weakness is an important etiological factor in plantar fasciitis (PF), but available data on the role of the quadriceps, hamstring, and gastrocnemius (GCM) muscles are limited. The aim of this study was to compare the strength and reaction time of the quadriceps, hamstring, and GCM muscles and foot pressure between patients with PF and normal controls.

Methods
A total of 21 PF patients and 21 normal controls were enrolled. Muscle strength was measured by the peak torque per body weight (Nmkg− 1 × 100). Muscle reaction time was evaluated by the acceleration time (AT, milliseconds). Foot pressure and posture were assessed by pedobarography [valgus/varus index (VV index), %].

Results
The strength of the quadriceps was significantly lower in the affected ankles of the PF group than in the control group (p = 0.005). The AT of the quadriceps and hamstring muscles was significantly increased in the affected ankles of the PF group than in the control group (quadriceps: p = 0.012, hamstring: p = 0.001), while the AT of the GCM muscle was significantly decreased (p = 0.009) and significantly correlated negatively with quadriceps muscle strength (r = −.598, p = 0.004) and AT (r = −.472, p = 0.031). Forefoot (p = 0.001) and hindfoot (p = 0.000) pressure were significantly greater, with the VV index showing hindfoot valgus, in the affected ankles in the PF group compared to the control group (p = 0.039).

Conclusions
This study demonstrated weakness and delayed reaction time of the quadriceps and hamstring muscles, with a rapid reaction time of the GCM muscle, in patients with PF.

Clinical relevance
Clinicians and therapists should assess the function of the quadriceps and hamstring muscles when planning the management of PF patients without muscle tightness.