Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial.

BACKGROUND: Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed. METHODS: Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR). RESULTS: A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49-0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors. CONCLUSIONS: Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients. TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.

Genomic Basis of Striking Fin Shapes and Colors in the Fighting Fish.

Resolving the genomic basis underlying phenotypic variations is a question of great importance in evolutionary biology. However, understanding how genotypes determine the phenotypes is still challenging. Centuries of artificial selective breeding for beauty and aggression resulted in a plethora of colors, long-fin varieties, and hyper-aggressive behavior in the air-breathing Siamese fighting fish (Betta splendens), supplying an excellent system for studying the genomic basis of phenotypic variations. Combining whole-genome sequencing, quantitative trait loci mapping, genome-wide association studies, and genome editing, we investigated the genomic basis of huge morphological variation in fins and striking differences in coloration in the fighting fish. Results revealed that the double tail, elephant ear, albino, and fin spot mutants each were determined by single major-effect loci. The elephant ear phenotype was likely related to differential expression of a potassium ion channel gene, kcnh8. The albinotic phenotype was likely linked to a cis-regulatory element acting on the mitfa gene and the double-tail mutant was suggested to be caused by a deletion in a zic1/zic4 coenhancer. Our data highlight that major loci and cis-regulatory elements play important roles in bringing about phenotypic innovations and establish Bettas as new powerful model to study the genomic basis of evolved changes.

FLZ attenuates learning and memory deficits via suppressing neuroinflammation induced by LPS in mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in which neuroinflammation plays an important role. FLZ is a novel synthetic derivative of natural squamosamide. Previous studies demonstrated that FLZ had neuroprotective effects on AD models and showed strong anti-inflammatory property in Parkinson's disease models. However, whether the neuroprotective effects of FLZ on AD are associated with its anti-inflammatory property is still not fully elucidated. In this study, we aimed to investigate the ability of FLZ in modulating inflammation. The results showed that FLZ significantly improved memory deficits and alleviated neuronal damage as well as neuronal loss in the hippocampus of mice intracerebroventricular injected with lipopolysaccharide (LPS). Mechanistic studies revealed that the neuroprotective effects of FLZ were due to the suppression of neuroinflammation induced by LPS, as indicated by inactivation of astrocytes and microglia, reduced production of tumor necrosis factor-α, interleukin-1ß, and nitric oxide, as well as decreased expression of cyclooxygenase-2 and inducible nitric oxide synthase. The beneficial effects of FLZ on AD were further supported by the finding that FLZ attenuated ß-amyloid production through inhibiting ß-amyloid precursor protein cleaving enzyme 1 expression. These results suggested that anti-inflammatory agent could be useful for the treatment of AD.

Construction of inflammatory associated risk gene prognostic model of NSCLC and its correlation with chemotherapy sensitivity.

BACKGROUND: Inflammation is an important pathogenic factor of most malignant tumors. It is essential to understand mechanism underlying inflammation and cancer development, so as to formulate and develop anti-cancer treatment strategies. However, inflammatory-related gene characterization as well as risk model construction in prognosis and response chemotherapy or immunotherapy in NSCLC are still remain unclear. METHODS: A total of 1014 lung cancer samples with RNA-seqencing results were download from The Cancer Genome Atlas (TCGA) database. The patient cohort was randomized as a training and test cohorts, and 200 inflammatory-related genes were selected based on previously published data. Consensus clustering and Enrichment and immune function analyses base on Differential expression genes (DEGs) were performed. Prognosis Prediction Model were Constructed and Chemotherapy and immunotherapy sensitivity base on this model were performed. At last, H1299 and HCC827 cells were used to tested the mitoxantrone and oxal iplatin sensitivity after KRT6A knockdown. RESULTS: We identified the inflammatory-related genes from NSCLC datasets to build one prognosis prediction signature based on cluster inflammatory-related genes to lay a certain foundation for distinguishing high-risk NSCLC cases with dismal prognostic outcome. The nomogram provides the AUC values for 1-, 3-, and 5-year overall survival were 0.831, 0.853, and 0.86 in validation cohort. Morover, different sensitivity of immunotherapy or chemotherapy also were classified base on the different risk groups in NSCLC patients, which provided potent clinical reference. At last, targeting KRT6A sensitive to mitoxantrone and oxaliplatin in H1299 and HCC827 cells. CONCLUSIONS: Inflammatory-related gene risk-score is the potential chemotherapeutic and immunotherapeutic biomarker for NSCLC, and targeting KRT6A sensitive to mitoxantrone and oxaliplatin in NSCLC.HighlightsInflammatory-related genes can lay a certain foundation for distinguishing high-risk NSCLC cases with dismal prognostic outcome.Risk-score base on inflammatory-related genes is positive correlated with CD274, TGFBR1 and TGFB1 expression.Targeting KRT6A sensitive to mitoxantrone and oxaliplatin in H1299 and HCC827 cells.

Compound FLZ inhibits lipopolysaccharide-induced inflammatory effects via down-regulation of the TAK-IKK and TAK-JNK/p38MAPK pathways in RAW264.7 macrophages.

AIM: The aim of this study was to investigate the effect of the squamosamide derivative FLZ (N-2-(4-hydroxy-phenyl)-ethyl-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) on lipopolysaccharide (LPS)-induced inflammatory mediator production and the underlying mechanism in RAW264.7 macrophages. METHODS: RAW264.7 cells were preincubated with non-toxic concentrations of compound FLZ (1, 5, and 10 micromol/L) for 30 min and then stimulated with 10 microg/L LPS. The production of nitric oxide (NO), the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), and the activation of nuclear factor kappa-B (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways were examined. RESULTS: FLZ significantly inhibited the LPS-induced production of NO, as well as the expression of iNOS and COX-2 at both the RNA and the protein levels in RAW264.7 cells. The LPS-induced increase in the DNA binding activity of NF-kappaB and activator protein 1 (AP-1), the nuclear translocation of NF-kappaB p65, the degradation of the inhibitory kappaBalpha protein (IkappaBalpha) and the phosphorylation of IkappaBalpha, IkappaB kinase (IKK) alpha/beta, c-Jun NH(2)-terminal kinase (JNK) and p38 MAPKs were all suppressed by FLZ. However, the phosphorylation of extracellular signal-regulated kinase (ERK) was not affected. Further study revealed that FLZ inhibited the phosphorylation of transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1), which is an upstream signaling molecule required for IKKalpha/beta, JNK and p38 activation. CONCLUSION: FLZ inhibited the LPS-induced production of inflammatory mediators at least partly through the downregulation of the TAK-IKK and TAK-JNK/p38MAPK pathways.

Mapping and Validating QTL for Fatty Acid Compositions and Growth Traits in Asian Seabass.

Asian seabass is an important food fish species. While improving growth, increasing the nutritional value is important, omega-3 fatty acids are indispensable to human health. Identifying and validating DNA markers associated with traits is the first step towards marker-assisted selection (MAS). We quantified 13 different fatty acids and three growth traits in 213 F2 Asian seabass from a family at the age 270 days post hatch, and screened QTL for these traits. The content of total fatty acids in 100 g flesh was 2.57 ± 0.80 g, while the proportions of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were 16.96 ± 2.20% and 5.42 ± 0.90%, respectively. A linkage map with 2424 SNPs was constructed and used for QTL mapping. For fatty acid compositions, 14 significant QTL were identified on three linkage groups (LG5, LG11 and LG14), with phenotypic variance explained (PVE) from 12.8 to 24.6%. Thirty-nine suggestive QTL were detected on 16 LGs. Two significant QTL for EPA were identified on LG5 and LG14, with PVE of 15.2% and 15.1%, respectively. No significant QTL was identified for DHA. For growth traits, six significant and 13 suggestive QTL were identified on two and seven LGs, respectively. Only a few significant QTL for fatty acids overlapped with previously mapped QTL for these traits, suggesting that most QTL detected in a family are family-specific and could only be used in MAS in the family per se. To facilitate population-wide molecular breeding, more powerful methods (e.g. GWAS) should be used to identify SNPs for genomic selection.

The prevalence and risk factors of venous thromboembolism in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease.

INTRODUCTION: Venous thromboembolism (VTE) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is not rare, which would affect the patient's prognosis. OBJECTIVES: To examine the prevalence, risk factors and clinical characteristics of AECOPD patients with VTE. METHODS: We performed this multi-center, prospective, observational study that involved 16 hospitals in China. Patients admitted to hospital due to AECOPD were consecutively enrolled. Baseline characteristics, VTE risk factors, symptoms, signs and auxiliary examination results were collected. Lower limb venous ultrasound and computed tomography pulmonary angiography were examined. RESULTS: Between June 2009 and October 2010, a total of 1144 AECOPD patients (the average age 72.0 ± 9.1 years, 761 males) were enrolled in this study. Seventy-eight (6.8%) were diagnosed with VTE, including 24 PE, 64 DVT, 10 combined PE and DVT. VTE patients were older than non-VTE patients. History of venous thromboembolism and lower extremity varicose vein, and presence of longer immobility (≥3 days), lower limbs problems of swelling, pain and walking difficulties, diuretics use, fever, syncope, higher d-dimer and lower hemoglobin were more common in VTE patients than in non-VTE patients. After adjusting the covariates, venous thrombosis history, prolonged immobility (≥3 days), lower limb pain before hospitalization, higher d-dimer independently associated with VTE development. Regular glucocorticoid use was not associated with increased risk of VTE in this set of patients. CONCLUSION: VTE is relatively common among hospitalized AECOPD patients. Conventional prophylactic anticoagulant therapy may be considered for those hospitalized AECOPD patients with risk factors.

Circularly permuted TRAIL plus thalidomide and dexamethasone versus thalidomide and dexamethasone for relapsed/refractory multiple myeloma: a phase 2 study.

PURPOSE: Circularly permuted TRAIL (CPT) has exhibited promising efficacy as a mono-therapy or in combination with thalidomide for patients with multiple myeloma (MM). In this phase 2 study, the safety and efficacy of CPT in combination with thalidomide and dexamethasone (CPT + TD) was evaluated in patients with pretreated relapsed/refractory MM (RRMM). METHODS: Patients who received at least two previous therapies for MM were randomly assigned at a 2:1 ratio to receive treatment with CPT + TD or thalidomide and dexamethasone (TD). The primary endpoint was the overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), duration of response (DOR) and safety. RESULTS: Overall, 47 patients were assigned to the CPT + TD group, and 24 patients were recruited to the TD group. The ORR in the CPT + TD group was 38.3 vs. 25.0% in the TD group. The median PFS time was 6.7 months for the CPT + TD group and 3.1 months for the TD group. The median DORs for the CPT + TD and TD groups were 7.1 and 3.2 months, respectively. Most of the adverse effects (AEs) were grade 1 or 2. Serious AEs were reported in 19.7% of the patients. No treatment-related deaths were reported. CONCLUSION: CPT plus TD could serve as a new therapeutic strategy for patients with RRMM. A randomized, double-blind, placebo-controlled confirmatory study is currently under way.