A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Patients with transfusion-dependent ß-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ß superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent ß-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 µg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent ß-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).

Xylobiose Prevents High-Fat Diet Induced Mice Obesity by Suppressing Mesenteric Fat Deposition and Metabolic Dysregulation.

Obesity is a public concern and is responsible for various metabolic diseases. Xylobiose (XB), an alternative sweetener, is a major component of xylo-oligosaccharide. The purpose of this study was to investigate the effects of XB on obesity and its associated metabolic changes in related organs. For these studies, mice received a 60% high-fat diet supplemented with 15% d-xylose, 10% XB, or 15% XB as part of the total sucrose content of the diet for ten weeks. Body weight, fat and liver weights, fasting blood glucose, and blood lipids levels were significantly reduced with XB supplementation. Levels of leptin and adipokine were also improved and lipogenic and adipogenic genes in mesenteric fat and liver were down-regulated with XB supplementation. Furthermore, pro-inflammatory cytokines, fatty acid uptake, lipolysis, and ß-oxidation-related gene expression levels in mesenteric fat were down-regulated with XB supplementation. Thus, XB exhibited therapeutic potential for treating obesity which involved suppression of fat deposition and obesity-related metabolic disorders.

A phase III, randomised, double-blind, multi-national clinical trial comparing SB12 (proposed eculizumab biosimilar) and reference eculizumab in patients with paroxysmal nocturnal haemoglobinuria.

Treatment of paroxysmal nocturnal haemoglobinuria (PNH) includes the monoclonal antibody eculizumab. This randomised, double-blind, multi-national cross-over Phase III study in PNH patients aimed to demonstrate the equivalence of the proposed eculizumab biosimilar SB12 and reference eculizumab (Soliris, ECU). PNH patients with lactate dehydrogenase (LDH) ≥1·5× upper limit of normal were randomised into treatment sequences SB12-ECU or ECU-SB12. Four weekly infusions of 600 mg eculizumab were followed by fortnightly infusions of 900 mg until week 50 (ECU/SB12 cross-over at week 26). Primary endpoints were LDH at week 26 and the time-adjusted area under the effect curve (AUEC) of LDH over weeks 14‒26 and 40‒52. Among 46 patients (92%) who completed the study, the least squares mean (LSM) difference in LDH at week 26 (34·48; 95% confidence interval [CI] -47·66‒116·62 U/l) and geometric LSM ratio of time-adjusted AUEC of LDH (1·08; 90% CI 0·95‒1·23) were within pre-defined equivalence margins. Mean numbers of transfused red blood cell units, other secondary endpoints, pharmacokinetics, and pharmacodynamics were comparable. No patients developed anti-drug antibodies. Treatment-emergent adverse events were reported in 72% and 68% of patients in the SB12 and ECU treatment groups, respectively. The results demonstrate equivalence of SB12 to ECU and support SB12-use in PNH patients.

Flexible, Elastic, and Superhydrophobic/Superoleophilic Adhesive for Reusable and Durable Water/Oil Separation Coating.

This study investigates a highly flexible/stretchable and mechanically durable superhydrophobic/superoleophilic coating for efficient oil/water separation and oil absorption. The coating is applied via a simple immersion process using a mixed solution of a biocompatible adhesive (ethyl cyanoacrylate, ECA), a highly stretchable polymer (polycaprolactone, PCL), and superhydrophobic/superoleophilic nanoparticles (fluorine-coated silica nanoparticles, F-SiO2 NPs) in a solvent, followed by solvent evaporation and ECA polymerization. Polymerized ECA (poly-ECA) in the coating material strongly adheres the F-SiO2 NPs to the substrate surface, while PCL bestows the rigid poly-ECA with high flexibility. A coated polyurethane sponge exhibits superhydrophobicity (water contact angle of >150°), while retaining robust mechanical stability and flexibility/elasticity. This provides an efficient means of cleaning oil spills with high selectivity, even after mechanical abrasion (>99% separation efficiency is retained after 120 tape test cycles and 50 rubbing test cycles), with excellent reusability.

Construction of a microRNA-mRNA Regulatory Network in De Novo Cytogenetically Normal Acute Myeloid Leukemia Patients.

Background: The association between dysregulated microRNAs (miRNAs) and acute myeloid leukemia (AML) is well known. However, our understanding of the regulatory role of miRNAs in the cytogenetically normal AML (CN-AML) subtype pathway is still poor. The current study integrated miRNA and mRNA profiles to explore novel miRNA-mRNA interactions that affect the regulatory patterns of de novo CN-AML. Methods: We utilized a multiplexed nanoString nCounter platform to profile both miRNAs and mRNAs using similar sets of patient samples (n = 24). Correlations were assessed, and an miRNA-mRNA network was constructed. The underlying biological functions of the mRNAs were predicted by gene enrichment. Finally, the interacting pairs were assessed using TargetScan and microT-CDS. We identified 637 significant negative correlations (false discovery rate <0.05). Results: Network analysis revealed a cluster of 12 miRNAs representing the majority of mRNA targets. Within the cluster, five miRNAs (miR-495-3p, miR-185-5p, let-7i-5p, miR-409-3p, and miR-127-3p) were posited to play a pivotal role in the regulation of CN-AML, as they are associated with the negative regulation of myeloid leukocyte differentiation, negative regulation of myeloid cell differentiation, and positive regulation of hematopoiesis. Conclusion: Three novel interactions in CN-AML were predicted as let-7i-5p:HOXA9, miR-495-3p:PIK3R1, and miR-495-3p:CDK6 may be responsible for regulating myeloid cell differentiation in CN-AML.

Perfluoropolyether-benzophenone as a highly durable, broadband anti-reflection, and anti-contamination coating.

Anti-reflection and anti-contamination coatings prepared from fluorinated polymers have widespread and important applications, ranging from protective films for corrosion resistance to high-tech microelectronics and medical devices due to their transparency, low refractive index, stain resistance, and antifouling properties. However, the application of existing coatings is hindered by low surface adhesion to the target substrate and weakness when exposed to mechanical stress or damage, resulting in significant limitations to their practical applications. Herein, we incorporate perfluoropolyether (PFPE) with benzophenone (BP) to develop an efficient coating material (PFPE-BP) possessing broadband anti-reflectivity, anti-contamination properties, excellent abrasion resistance, and stability under elevated temperatures and relative humidity. The presence of BP allows the coating materials to be homogeneously mixed with a commercial hard coating solution to uniformly coat the target substrate. Furthermore, UV light irradiation on the coating surface results in excellent adhesion between BP groups of PFPE-BP and the hard coating matrix.

Clinical features and treatment outcomes of Hodgkin lymphoma: A retrospective review in a Malaysian tertiary hospital.

BACKGROUND: Classical Hodgkin lymphoma (cHL) is a clinicopathologically unique, aggressive lymphoma arising from germinal center B-cells and is one of the most curable hematological malignancies. This study aimed to determine the clinical course, treatment regimens, response rates, and survival data of patients diagnosed with cHL in a tertiary center. METHODS: A retrospective review was conducted to include patients with a diagnosis of cHL from 2013 to 2017. Data of demographic and clinical characteristics, treatment regimens, and outcomes were collected and analyzed. RESULTS: We recruited 94 patients with a median age of 27.0 [interquartile range (IQR), 12] years. Most of the patients were male (61.7%) and 73.4% were ethnic Malay. Nodular sclerosis was the most common histology (77.6%), followed by mixed cellularity (6.4%) and others (16%). The median follow-up time was 28.0 (IQR, 32) months. All patients received chemotherapy but only 13.8% received radiotherapy as consolidation. The doxorubicin-bleomycin-vinblastine-dacarbazine regimen was the most common (85.1%), followed by the escalated bleomycin-etoposide-doxorubicin-cyclophosphamide-vincristineprednisolone-procarbazine regimen (14.9%). Following treatment, 76.1% of patients achieved complete response. The 2-year overall survival (OS) and progression-free survival (PFS) of the entire cohort were 96.5% and 71.1%, respectively. The 2-year OS and PFS for advanced-stage disease were 93.9% and 62.8%, compared to 100% and 82.7% for early-stage disease, respectively (P=0.252 and P=0.052, respectively). CONCLUSION: This study provides insight into the clinical presentation and treatment outcomes among patients with cHL in Malaysia. A longer study duration is required to identify OS and PFS benefits and treatment-related complications for different chemotherapeutic regimens.

Acquired Hemophilia of Unknown Etiology in an Elderly Man: Case Report.

BACKGROUND Acquired hemophilia is a rare but potentially dangerous bleeding disorder caused by autoantibodies against coagulation factors. It affects 1 to 1.5 per 1 million people each year. While 50% of cases could be idiopathic, other causes include malignancies, diabetes, pregnancy, infection, and autoimmune disorders. CASE REPORT We report a case of a 90-year-old male who developed a spontaneous hematoma on the dorsum of his right hand, with no prior history of trauma or any other mucosal bleeding. His activated partial thromboplastin time (aPTT) was found to be prolonged (>180 seconds) with a very low level of factor VIII (0.1%). CONCLUSIONS As workups did not identify the source, including malignancy and autoimmune diseases, of his acquired hemophilia, it is believed to be idiopathic. He was started on intravenous recombinant factor VIIa (NovoSeven) to control the bleeding in combination with an immunosuppressive therapy of cyclophosphamide and prednisolone. In approximately 10% of patients with acquired hemophilia, underlying malignancy, such as squamous cell cancer, chronic lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma can present and commonly develop in elderly patients. Therefore, patients diagnosed with idiopathic acquired hemophilia should be given long-term follow up.

The epidemiology and clinical characteristics of myeloproliferative neoplasms in Malaysia.

BACKGROUND: The evolution of molecular studies in myeloproliferative neoplasms (MPN) has enlightened us the understanding of this complex disease consisting of polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The epidemiology is well described in the western world but not in Asian countries like Malaysia. MATERIALS AND METHODS: This retrospective national registry of MPN was conducted from year 2009 to 2015 in Malaysia. RESULTS: A total of 1010 patients were registered over a period of 5 years. The mean age was 54 years with male predominance. The ethnic distribution revealed that Chinese had a relatively high weighted incidence proportion (43.2%), followed by Indian (23.8%), Malay (15.8%) and other ethnic groups (17.2%). The types of MPN reported were 40.4% of ET (n = 408), 38.1% of PV (n = 385), 9.2% of PMF (n = 93), 3.1% of hypereosinophilic syndrome (HES) (n = 31) and 7.9% of unclassifiable MPN (MPN-U) (n = 80). Splenomegaly was only palpable clinically in 32.2% of patients. The positive JAK2 V617F mutation was present in 644 patients with 46.6% in PV, 36.0% in ET, 9.0% in PMF, and 7.4% in MPN-U, and had significantly lower haemoglobin (p < 0.001), haematocrit (p < 0.001) and white blood cells (WBC) (p < 0.001) than those with negative mutation. Significant differences in platelet and WBC count were detected in ethnic groups and MPN sub-types. There were more arterial thrombosis events seen in those with JAK2 V617F mutation as compared to venous thrombosis events (23.1% vs 4.4%). The bleeding rate was only 6.6%. Among the risk factors, previous thrombosis, old age (≥ 60 years) and hypertension were significantly correlated to positive JAK2 V617F mutation. The arterial thrombosis event is associated with higher presenting HB, HCT and PLT while the bleeding event is associated with lower presenting HB, HCT but higher PLT. The presence of JAK2 V617F mutation is associated with higher risk of arterial thrombosis. CONCLUSION: Chinese ethnicity is associated with higher rates of MPN. The history of thrombosis, age ≥ 60 years and hypertension are risk factors that can be correlated to JAK2 V617F mutation. This study is instrumental for policy makers to ensure preventive strategies can be implemented in future.

Phyllodulcin, a Natural Sweetener, Regulates Obesity-Related Metabolic Changes and Fat Browning-Related Genes of Subcutaneous White Adipose Tissue in High-Fat Diet-Induced Obese Mice.

Phyllodulcin is a natural sweetener found in Hydrangea macrophylla var. thunbergii. This study investigated whether phyllodulcin could improve metabolic abnormalities in high-fat diet (HFD)-induced obese mice. Animals were fed a 60% HFD for 6 weeks to induce obesity, followed by 7 weeks of supplementation with phyllodulcin (20 or 40 mg/kg body weight (b.w.)/day). Stevioside (40 mg/kg b.w./day) was used as a positive control. Phyllodulcin supplementation reduced subcutaneous fat mass, levels of plasma lipids, triglycerides, total cholesterol, and low-density lipoprotein cholesterol and improved the levels of leptin, adiponectin, and fasting blood glucose. In subcutaneous fat tissues, supplementation with stevioside or phyllodulcin significantly decreased mRNA expression of lipogenesis-related genes, including CCAAT/enhancer-binding protein α (C/EBPα), peroxisome proliferator activated receptor γ (PPARγ), and sterol regulatory element-binding protein-1C (SREBP-1c) compared to the high-fat group. Phyllodulcin supplementation significantly increased the expression of fat browning-related genes, including PR domain containing 16 (Prdm16), uncoupling protein 1 (UCP1), and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), compared to the high-fat group. Hypothalamic brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) signaling was upregulated by phyllodulcin supplementation. In conclusion, phyllodulcin is a potential sweetener that could be used to combat obesity by regulating levels of leptin, fat browning-related genes, and hypothalamic BDNF-TrkB signaling.