Modulation of sirtuins during monolayer chondrocyte culture influences cartilage regeneration upon transfer to a 3D culture environment

This study examined the role of sirtuins in the regenerative potential of articular chondrocytes. Sirtuins (SIRT1-7) play a key role in regulating cartilage homeostasis. By inhibiting pro-inflammatory pathways responsible for cartilage degradation and promoting the expression of key matrix components, sirtuins have the potential to drive a favourable balance between anabolic and catabolic processes critical to regenerative medicine. When subjected to osmolarity and glucose concentrations representative of the in vivo niche, freshly isolated bovine chondrocytes exhibited increases in SIRT1 but not SIRT3 gene expression. Replicating methods adopted for the in vitro monolayer expansion of chondrocytes for cartilage regenerative therapies, we found that SIRT1 gene expression declined during expansion. Manipulation of sirtuin activity during in vitro expansion by supplementation with the SIRT1-specific activator SRT1720, nicotinamide mononucleotide, or the pan-sirtuin inhibitor nicotinamide, significantly influenced cartilage regeneration in subsequent 3D culture. Tissue mass, cellularity and extracellular matrix content were reduced in response to sirtuin inhibition during expansion, whilst sirtuin activation enhanced these measures of cartilage tissue regeneration. Modulation of sirtuin activity during monolayer expansion influenced H3K27me3, a heterochromatin mark with an important role in development and differentiation. Unexpectedly, treatment of primary chondrocytes with sirtuin activators in 3D culture reduced their matrix synthesis. Thus, modulating sirtuin activity during the in vitro monolayer expansion phase may represent a distinct opportunity to enhance the outcome of cartilage regenerative medicine techniques

Change in patient-reported outcomes in single-unit transfusion comparable with double-unit transfusion

Session - 401. Basic Science and Clinical Practice in Blood Transfusion: Poster 2: Paper 93706INTRODUCTION: Patient blood management was developed to reduce allogeneic blood exposure and enhance patient outcomes. If transfusion is required in stable and non-bleeding hospitalized patients, prescribing one unit of red blood cells (RBC) followed by reassessment of clinical condition is recommended. Double-unit RBC transfusion, the routine practice in the past, is still widely practiced despite the advocate of restrictive transfusion strategy. One of the reasons could be a ...postprin

Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome

Clinical outcome and mutations of 96 core-binding factor acute myeloid leukemia (AML) patients 18-60 years old were examined. Complete remission (CR) after induction was 94.6%. There was no significant difference in CR, leukemia-free-survival (LFS) and overall survival (OS) between t(8;21) (N=67) and inv(16) patients (N=29). Univariate analysis showed hematopoietic stem cell transplantation at CR1 as the only clinical parameter associated with superior LFS. Next-generation sequencing based on a myeloid gene panel was performed in 72 patients. Mutations in genes involved in cell signaling were associated with inferior LFS and OS, whereas those in genes involved in DNA methylation were associated with inferior LFS. KIT activation loop (AL) mutations occurred in 25 patients, and were associated with inferior LFS (P=0.003) and OS (P=0.001). TET2 mutations occurred in 8 patients, and were associated with significantly shorter LFS (P=0.015) but not OS. Patients negative for KIT-AL and TET2 mutations (N=41) had significantly better LFS (P<0.001) and OS (P=0.012) than those positive for both or either mutation. Multivariate analysis showed that KIT-AL and TET2 mutations were associated with inferior LFS, whereas age ⩾40 years and marrow blast ⩾70% were associated with inferior OS. These observations provide new insights that may guide better treatment for this AML subtype.published_or_final_versio

Antimicrobial prophylaxis and post-chemotherapy neutropenic fever in patients with leukemia : comparisons of C-reactive protein, procalcitonin and immediate fever outcome measures between those with and without prophylaxis, and the implications for practice

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Factors affecting patient-reported outcomes after red blood cell transfusion in medical patients

BACKGROUND Physical variables like mortality or cardiac events were used to evaluate the requirement of red blood cell (RBC) transfusion. However, patient-reported outcomes (PROs) of blood transfusion recipients were seldom assessed. The health-related quality of life (HRQoL) of patients before and after RBC transfusion was compared in this study. STUDY DESIGN AND METHODS The study period was February to June 2016. Standardized generic and anemia symptom-specific HRQoL instruments were administered to patients receiving RBC transfusion in the medical unit of a single center. The primary outcome was the change in HRQoL scores on Days 1 and 7 posttransfusion from baseline values on the day of transfusion (Day 0). Multiple linear regression analysis was performed to study the effect of transfusion strategy and other factors on PRO. RESULTS The analysis included 99 general medical patients. The median (interquartile range) pretransfusion hemoglobin level was 72 (66-78) g/L. Two or more units of RBCs were prescribed to 45 patients (45%) on Day 0. Functional Assessment of Cancer Therapy-Anemia Subscale improved significantly on Days 1 and 7 by effect sizes of 0.41 and 0.38, respectively (p < 0.001). Regression analysis showed that lower baseline HRQoL scores were associated with better PRO on both Day 1 and Day 7 (p < 0.001). Transfusion trigger and number of RBC units transfused did not affect the change in HRQoL. CONCLUSION Worse pretransfusion HRQoL is a predictor of improvement in PRO after blood transfusion. There is no evidence that a restrictive transfusion or single-unit policy jeopardizes PRO

Oral arsenic trioxide-based maintenance regimens for first complete remission of acute promyelocytic leukemia: A 10-year follow-up study

Seventy-six patients with acute promyelocytic leukemia (APL) in first complete remission after induction and consolidation by daunorubicin and cytosine arabinoside received oral arsenic trioxide (As 2O 3)-based maintenance. Three regimens were used: oral As 2O 3 (10 mg/day, regimen A, n ∇ 20), oral As 2O 3 plus all-trans retinoic acid (ATRA, 45 mg/m 2 per day, regimen AA, n ∇ 19), and oral As 2O 3plus ATRA plus ascorbic acid (1000 mg/day, regimen AAA, n ∇ 37), each given for 2 weeks every 2 months for 2 years. Patients receiving A, AA, and AAA maintenance did not differ significantly in clinicopathologic features and risk factors. Headache, dyspepsia, reversible liver function derangement, and herpes zoster reactivation were adverse effects observed during maintenance. QTc prolongation and arrhythmias were not encountered. At a median follow-up of 24 months (range, 1-115 months), there were 8 relapses. The 3-year leukemia-free-survival, event-free-survival, and overall-survival were 87.7%, 83.7%, and 90.6%, respectively. Adverse prognostic factors included male gender for leukemia-free-survival, and unrelated cancers for overall survival. Age, presentation WBC count and platelet count, and the type of oral As 2O 3 maintenance regimens had no impact on survivals. Prolonged oral As 2O 3 maintenance was feasible and safe and resulted in favorable outcomes when used with a simple induction and consolidation regimen compared with other protocols composed of multiple chemotherapeutic agents. © 2011 by The American Society of Hematology.link_to_subscribed_fulltex

A cross-sectional magnetic resonance imaging assessment of organ specific hemosiderosis in 180 thalassemia major patients in Hong Kong

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