bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osteochondral Allograft Transplantation for Osteochondritis Dissecans of the Medial Femoral Condyle
Authors: Torres LeeAnne , Dennis Eric , Dogariu Lauren , Waterman Brian R. 
Published: April 2021

Background: While the data are not as robust as in the adult population, osteochondral allograft transplantation has proven to be an effective treatment for osteochondritis dissecans (OCD) lesions of the knee in the pediatric and adolescent populations. Indications: The primary indication for osteochondral allograft transplantation is a symptomatic, full-thickness, localized cartilage lesion. Acceptable underlying causes include trauma, avascular necrosis, and OCD lesions. As these are pediatric and adolescent patients, they are not candidates for joint arthroplasty. In this case, the patient is a 16-year-old girl with a 1.5 cm × 1.2 cm OCD lesion of the medial femoral condyle. Technique Description: The patient was positioned supine with a tourniquet on the thigh. The lesion was identified on the medial femoral condyle and exposed. A guidepin was placed in the center of the lesion and a 15 mm reamer was used to ream to a depth of 6 to 7 mm. The wound was copiously irrigated. A corresponding 15 mm plug was harvested from the donor graft and prepared to match the morphology of the condyle. The 12 o’clock position was marked with a fresh marking pen to maintain orientation. The graft was lavaged with a pulsavac and bathed in autologous conditioned plasma. The recipient bed was prepared with 0.0045 K wire, and then the donor graft was placed in proper position and impacted with a tamp, flush with the surrounding cartilage. The tourniquet was deflated and the surgical site was closed in a layered fashion. Results: Studies of adult patients have demonstrated survival rates of greater than 80% for osteochondral allograft transplantation, with pain improvement of 74% to 85%, and return to competitive athletics of 88%. While there is a paucity of studies looking at osteochondral allograft transplantation in pediatric and adolescent populations, outcomes appear to be similar to that of the adult population. Discussion/Conclusion: Osteochondral allograft transplantation is a viable treatment option for pediatric and adolescent patients with symptomatic cartilage lesions. It allows for joint preservation and provides significant improvement of pain with high rates of return to athletics.
Emerging therapies for inv(16) AML
Authors: Surapally Sridevi , Tenen Daniel G. , Pulikkan John A. 
Published: April 2021

Abstract
The core binding factor composed of CBFβ and RUNX subunits plays a critical role in most hematopoietic lineages and is deregulated in acute myeloid leukemia (AML). The fusion oncogene CBFβ-SMMHC expressed in AML with the chromosome inversion inv(16)(p13q22) acts as a driver oncogene in hematopoietic stem cells and induces AML. This review focuses on novel insights regarding the molecular mechanisms involved in CBFβ-SMMHC–driven leukemogenesis and recent advances in therapeutic approaches to target CBFβ-SMMHC in inv(16) AML.
The bidirectional increased risk of B-cell lymphoma and T-cell lymphoma
Authors: Chihara Dai , Dores Graça M. , Flowers Christopher R. , Morton Lindsay M. 
Published: April 2021

Abstract
Lymphoma survivors have a significantly higher risk of developing second primary lymphoma than the general population; however, bidirectional risks of developing B- and T-cell lymphomas (BCLs and TCLs) specifically are less well understood. We used population-based cancer registry data to estimate the subtype-specific risks of second primary lymphoma among patients with first BCL (n = 288 478) or TCL (n = 23 747). We observed nearly fivefold increased bidirectional risk between BCL and TCL overall (TCL following BCL: standardized incidence ratio [SIR] = 4.7, 95% confidence interval [CI] = 4.2-5.2; BCL following TCL: SIR = 4.7, 95% CI = 4.1-5.2), but the risk varied substantially by lymphoma subtype. The highest SIRs were observed between Hodgkin lymphoma (HL) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (PTCL-NOS following HL: SIR = 27.5; HL following PTCL-NOS: SIR = 31.6). Strikingly elevated risks also were notable for angioimmunoblastic T-cell lymphoma (AITL) and diffuse large B-cell lymphoma (DLBCL) (AITL following DLBCL: SIR = 9.7; DLBCL following AITL: SIR = 15.3). These increased risks were strongest within the first year following diagnosis but remained persistently elevated even at ≥5 years. In contrast, SIRs were &lt;5 for all associations of TCL with chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. These patterns support etiologic heterogeneity among lymphoma subtypes and provide further insights into lymphomagenesis.
Oral Arsenic Plus Retinoic Acid Versus Intravenous Arsenic Plus Retinoic Acid for Non-High Risk Acute Promyelocytic Leukemia: A Multicenter Randomized Controlled Trials
Authors: Zhu Honghu , Wu Depei , Zhang Xi , LIU Lin , Ma Jun , Shao Zonghong , Ren Hanyun , Hu Jianda , Xu Kailin , Wang Jing-Wen , Song Yongping , Fang Mei-Yun , Huang Xiao-Jun 
Published: April 2021

Abstract
Objective
Intravenous arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non high-risk acute promyelocytic leukemia (APL), resulting in cure rates exceeding 95%. Pilot study of treatment with oral arsenic named the Realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy has shown high efficacy, convenient and economical. This randomized, multicenter, phase 3 noninferiority trial was designed to test the efficacy and safety of an oral RIF and ATRA compared with intravenous ATO for newly diagnosed non high-risk APL patients.
Methods
We conducted a phase 3, multicenter trial comparing RIF plus ATRA with ATO plus ATRA in patients with non high-risk APL (white-cell count, ≤10×109 per liter) between 2014 and 2017. In all, 109 patients were randomly assigned (2:1) to oral RIF (60 mg/kg) plus ATRA (25 mg/m2) or ATO (0.16mg/kg) plus ATRA (25 mg/m2) as induction therapy until complete hematologic remission. Postremission therapy included RIF or ATO on a schedule of 4 weeks on and 4 weeks off and ATRA on a schedule of 2 weeks on and 2 weeks off for 7 months.
The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival (EFS) at 2 years in the two groups was not greater than 10%.
Results
Complete remission was achieved in all 69 patients in the RIF-ATRA group who could be evaluated (3 withdraw during the induction) and in 34 of 36 patients in the ATO-ATRA group (2 died and another one withdraw during the induction) (100% vs. 94.4%, p= 0.12).
The median follow-up was 32 months. Two-year EFS rates were 97.1% in the RIF-ATRA group (n=69) and 94.4% in the ATO-ATRA group (n=36). The EFS rate difference was 2.7% (95% CI,-5.8% to11.1%). The lower limit of the 95%CI for EFS rate difference was greater than-10% noninferiority margin, confirming noninferiority (noninferiority P=0.0017). There is no difference about relapse rate and overall survival between two groups (all p &gt;0.05).
Conclusions
RIF plus ATRA is not inferior to ATO plus ATRA in the treatment of patients with non high-risk APL (Chinese Clinical Trial Registry number, ChiCTR-TRC-13004054).

Disclosures
No relevant conflicts of interest to declare.
Catalytically Active UCH-L1 Is Required for MYC Driven B-Cell Lymphomagenesis
Authors: Bedekovics Tibor , Hussain Sajjad , Galardy Paul J. 
Published: April 2021

Abstract
Mature B-cell lymphomas are common in children and adults. While increasing biological knowledge has greatly improved the classification of these diseases, the ability to stratify therapy based on this knowledge is limited. As the outcomes for patients with relapsed/refractory disease is poor, it is important to optimize the upfront approach to these patients making enhanced biomarker discovery essential. We recently found that the de-ubiquitinase UCH-L1 is strongly induced in normal GC B-cells, is highly expressed in germinal center type diffuse large B-cell lymphoma, and is a potent prognostic factor associated with poor outcomes in this disease. Using transgenic mice (Uchl1Tg), we observed that deregulated UCH-L1 drives spontaneous B-cell lymphomagenesis and significantly accelerates disease when combined with the Iμ-HABCL6 or Eμ- myc models of GC derived lymphoma. At the molecular level, we showed that UCH-L1 regulates mTOR complex assembly and promotes AKT signaling. It has been alternatively hypothesized that stabilization of mono-ubiquitin is an essential function of UCH-L1 - a mechanism that does not require catalytic activity. To determine the impact of UCH-L1 catalytic activity on lymphoma development, we generated mice carrying a catalytically inactive transgene (Uchl1TgC90A). Consistent with our prior work, we observed that UCH-L1 promotes AKT phosphorylation and suppresses mTORC1 activity towards 4EBP1 and S6K in splenocytes in a manor dependent on catalytic activity. To examine the impact on lymphomagenesis, we crossed Uchl1Tg and Uchl1TgC90A mice with the Eμ- myc model. While we again found the wild-type transgene to accelerate Myc driven lymphoma development, there was no such effect of the C90A construct, indicating that the catalytic activity of UCH-L1 is required for its oncogenic activity. To further examine its role in MYC driven lymphomagenesis we crossed Eμ- myc mice with homozygous null Uchl1 mice and found that Uchl1 loss leads to a significant improvement in lymphoma free survival, indicating that UCH-L1 is a key cooperating factor with MYC in lymphoma. Consistent with this, gene expression profiling from lymphomas arising in Uchl1Tg mice share a striking similarity to those driven by MYC and constitutive PI3 kinase signaling (MYC/P110*) but are distinct from those seen in Iμ-HABCL6 or Lig4 null mice. These data indicate an mechanistic interplay between UCH-L1 and MYC in B-cell lymphoma and suggest that UCH-L1 inhibition may be an effective approach in B-cell lymphomas expressing MYC.

Disclosures
Galardy: Mission Therapeutics: Research Funding; Abvie: Equity Ownership; Abbot labs: Equity Ownership.
Acute Chest Syndrome Among Hospitalized Children with Vaso-Occlusive Crisis: A Nationwide Study in the United States
Authors: Takahashi Takuto , Okubo Yusuke , Handa Atsuhiko , Miller Scott T. 
Published: April 2021

Abstract

Background: Acute chest syndrome (ACS) remains a leading cause of mortality among children with sickle cell disease (SCD); overall, nearly 50% of ACS is diagnosed during hospitalizations for other complications including painful vaso-occlusive crises (VOC).
Methods: The present study assesses epidemiological features of children hospitalized with VOC and evaluates factors potentially associated with development of ACS utilizing the large national all-payer Kid's Inpatient Database over a recent 9 year period. Records of children (age &lt; 20 years) were reviewed from 2003, 2006, 2009, and 2012) and multivariable logistic regression was used to assess risk factors and adjust for patient and hospital characteristics.
Results: Total annual hospitalization rates with VOC were variable, ranging from 26.4 per 100,000 children in 2009 to 29.5 in 2012. Multivariable logistic regression analysis showed children age 5-9 years had 2.38 times higher odds of developing ACS than children age 15-19 (95%CI, 2.22 to 2.56). Comorbidity of asthma was a risk factor for ACS (OR, 1.44; 95%CI, 1.36 to 1.53). ACS was as common in Hb SC patients hospitalized for VOC as those with SS.
Conclusion: These data demonstrate that despite increasing use of hydroxyurea in children shown in other reports, there has been no reduction in hospitalization rate for pain, and even young children are at risk for ACS. Though de novo ACS is less common in Hb SC, vigilance and prophylactic measures are required for those hospitalized for pain. Further studies are needed to assess the efficacy of prophylactic interventions including bronchodilator therapy for asthmatics hospitalized for VOC.

Disclosures
Miller: Pfizer Pharmaceutical: Research Funding.
The Impact of Electrical Calf Muscle Stimulation on the Residual Venous Obstruction and DVT Recurrence after Cessation of Standard Anticoagulation
Authors: Lobastov Kirill , Ryzhkin Vladimir , Vorontsova Athena , Schastlivtsev Iliya , Barinov Victor , Laberko Leonid , Rodoman Grigory 
Published: April 2021

Abstract
Aim. To assess the efficacy of electrical calf muscle stimulation (EMS) in patients with post-thrombotic syndrome (PTS) and residual venous obstruction (RVO) after cessation of a standard anticoagulation.
Methods. This was a prospective comparative clinical trial with masked outcome assessor involving patients after the first episode of unprovoked femoro-popliteal DVT who have completed a standard 6-month course of anticoagulation and had signs of RVO in the affected veins and Villalta score of 5 and more.
Totally were enrolled 60 patients in the age of 40-86 years (mean - 58,5 ± 11,4), 38 men and 22 women, divided into two groups of 30 participants. In both groups (main and control) PTS was treated by active walking (at least 5,000 steps per day controlled by an individual pedometer), below-knee graduated compression stockings (23-32 mm Hg) and micronized purified flavonoid fraction (2-month course twice a year). In the main group, EMS with «Veinoplus VI» device (3 procedures of 30 minutes every day) also was used. The main endpoint of the study was symptomatic or asymptomatic recurrent venous thrombosis confirmed by duplex ultrasound (DUS). The additional criteria of treatment efficacy were changes in the degree of current venous stenosis. The patients were followed up for 12 months with monthly DUS, aimed to reveal recurrent DVT, and 6-monthly DUS with evaluation of stenosis degree.
Results. RVO was represented by an average of 48%-stenosis of the common femoral vein in 12 patients, 53%-stenosis of the superficial femoral vein in 16 cases and 55%-stenosis of the popliteal vein in all participants. Through 12-month follow up the degree of stenosis decreased in all affected veins in both groups (p&lt;0,05). The most vivid dynamics was found in the popliteal vein: 60.8% - 55.1% - 28.8% in the main group and 50.9% - 30.1% - 27.3% in the control group (p&lt;0,0001) with significant differences between the groups (p=0.004)
Recurrence of venous thrombosis was found in 7 of 30 patients in the control group and in 0 of 30 patients in the main group (23.3% vs 0%, p=0.011). In 5 cases the recurrent DVT was silent and revealed by regular DUS and only in 2 cases it had a clinical manifestation. 4 of 5 silent cases were presented with re-occlusion of the early affected vein.
Conclusions. There is an ongoing process of deep veins recanalization during 12 months after cessation of anticoagulation in patients with RVO and PTS. Using of EMS in complex treatment of PTS allows to reduce the rate of recurrent DVT and increase the speed of recanalization.

Disclosures
Lobastov: "Gemakor Labs" Ltd: Honoraria, Research Funding; "BEHO+" Ltd: Honoraria, Research Funding. Ryzhkin: "BEHO+" Ltd: Research Funding. Laberko: "Gemakor Labs" Ltd: Honoraria, Research Funding; "BEHO+" Ltd: Honoraria. Rodoman: "Gemakor Labs" Ltd: Research Funding.
Comparative Risk of Acute Kidney Injury with Oral Anticoagulant Use Among Patients with Nonvalvular Atrial Fibrillation
Authors: Klil-Drori Adi J. , Azoulay Laurent , Nie Rui , Renoux Christel , Nessim Sharon J. , Filion Kristian B. 
Published: April 2021

Abstract
Background: Acute kidney injury (AKI) is common in patients with nonvalvular atrial fibrillation (NVAF) taking oral anticoagulants (OAC), especially in those with underlying chronic kidney disease (CKD). However, little is known on the comparative risk of AKI with the use of different OAC, including the direct acting oral anticoagulants (DOACs).
Methods: We conducted a population-based cohort study using the administrative healthcare databases of Quebec, Canada. Patients with NVAF who were new users of oral anticoagulants between 2011 and 2014 were followed for hospitalized AKI, stratified by CKD status. Hazard ratios (HR) and corresponding 95% CI for hospitalized AKI with the use of dabigatran, rivaroxaban, and apixaban versus warfarin and versus each other in pairwise analyses, were assessed using Cox proportional hazards models. Estimates were stratified by the deciles of a disease risk score for AKI obtained from a historic cohort of 25,513 warfarin users with NVAF. The disease risk score included important demographic and clinical covariates weighted by their association with AKI.
Results: Our cohort of 26,357 patients with NVAF included 22,084 without, and 4273 with CKD. The rates of AKI hospitalization were 3.2 (95% CI 2.9-3.4) and 16.5 (95% CI 15.3-17.9) per 100 person-years, respectively. Among patients without CKD, apixaban (HR, 0.25; 95% CI, 0.14-0.44), rivaroxaban (HR, 0.50; 95% CI, 0.40-0.64), and dabigatran (HR, 0.68; 95% CI 0.57-0.81) were associated with a decreased risk of AKI compared with warfarin (Table 1). Similar findings were observed in the CKD cohort (Table 2). Compared with apixaban, dabigatran was associated with increased AKI risk in patients without (HR, 2.58; 95% CI, 1.42-4.67) and with (HR, 2.08; 95% CI, 1.01-4.26) CKD, as was rivaroxaban (without CKD - HR, 2.29 [95% CI, 1.24-4.20]; with CKD - HR, 1.98 [95% CI, 0.95-4.11]). Rivaroxaban was associated with decreased risk of AKI in patients without CKD (HR, 0.76; 95% CI, 0.58-0.99), compared with dabigatran.
Conclusions: Use of all DOACs was associated with decreased risk of AKI compared with warfarin. Apixaban was associated with the lowest comparative risk of AKI among DOACs, and rivaroxaban was suggested to be more protective than dabigatran in patients without CKD. While these findings await further confirmation, worsening renal function while on DOAC treatment has been associated with increased risk of major bleeding. Thus, suggested differences in the renal safety of DOACs should be incorporated in informed prescription and monitoring of these drugs.

Disclosures
Renoux: Bayer Pharmaceuticals: Research Funding; Canadian Foundation for Innovation: Research Funding.
Recreation of Fetal Neonatal Alloimmune Thrombocytopenia in CRISPR/Cas9 Gene-Edited Mice Expressing the Human Platelet Alloantigen, HPA-1a
Authors: Zhi Huiying , Ahlen Maria Therese , Skogen Bjørn , Newman Peter 
Published: April 2021

Abstract
Fetal neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening alloimmune disorder caused by maternal antibodies directed against fetal platelet alloantigens. The human platelet alloantigens, (HPA)-1a/HPA-1b (also known as the PlA1 alloantigen system), residing on the integrin β3 subunit (= platelet membrane glycoprotein IIIa), is the most frequently implicated HPA for causing FNAIT in Caucasians, and a single Leu33Pro amino acid polymorphism is responsible for generating the HPA-1a and HPA-1b epitopes. Neither human nor mouse anti-HPA-1a antibodies recognize murine GPIIIa due to amino acid differences both within and surrounding the polymorphic amino acid, which lies within a long flexible loop in PSI domain of the molecule. As a result, there are currently no authentic mouse models of FNAIT capable of recapitulating the human alloimmune response to this clinically-important platelet antigen. We employed CRISPR/Cas9 gene editing technology to generate mice expressing the human HPA-1a allogeneic epitope. Four critical amino acid substitutions (A30P32L33D39) were introduced into the PSI domain of murine GPIIIa. The resulting humanized form of murine GPIIIa, termed APLD, reacted in a variety of immunoassays with both murine monoclonal (mAb) and human maternal polyclonal antibodies specific for the human HPA-1a epitope. Intraperitoneal injection of an anti-HPA-1a mAb induced thrombocytopenia in APLD, but not wild-type, mice. Importantly, wild-type mice immunized with murine APLD transgenic platelets generated a high-titer HPA-1a-specific antibody response, demonstrating that the humanized form of murine GPIIIa is immunogenic in mice. Finally, pre-immunized female wild-type mice bred with APLD males gave birth to neonatal mice that exhibited profound thrombocytopenia, with the maternal titer directly related to the degree of thrombocytopenia in the neonates. Recapitulating the essential features of FNAIT in mice will facilitate the investigation of a wide-range of clinically-important issues in the diagnosis, treatment, and management of platelet alloimmune disorders.

Disclosures
No relevant conflicts of interest to declare.
Examining the CREB Transcriptional Program in Erythropoiesis
Authors: Chung Jacky , Paw Barry H. , Lodish Harvey , Ghamari Alireza , Cantor Alan B. 
Published: April 2021

Abstract
The erythropoietin (EPO) signal transduction network regulates a plethora of critical cellular functions during red blood cell maturation including proliferation and iron metabolism. Recently, it has been discovered that EPO signaling also controls heme metabolism through activation of the protein kinase A (PKA) pathway. The activation of PKA by EPO leads to the mitochondrial phosphorylation of the terminal heme enzyme, ferrochelatase (FECH), to ramp up heme production. In addition to FECH, a second principal PKA target is the CREB transcription factor, leading to the hypothesis that the EPO-PKA signaling pathway also regulates gene expression during red cell maturation. Here, we tested this hypothesis using biochemical and bioinformatics approaches. We found that CREB becomes phosphorylated in human and murine erythroid cells in an EPO-dependent manner. Using pharmacologic inhibitors, we confirmed that CREB phosphorylation is downstream of JAK2 and PKA signaling. Moreover, we found enrichment of a previously identified CREB-gene signature within the erythroid transcriptional program. To date, our work suggests that CREB plays a role during red cell development as an effector of EPO signaling. Further work will be required to understand the function of CREB target genes.

Disclosures
No relevant conflicts of interest to declare.