RESUMO
The prevalence and distribution of chlorinated paraffins (CPs) have been extensively studied in various matrices and organisms; however, there is a lack of information about insects, particularly in honeybees. To address this gap, we studied young honeybee workers exposed to short- and medium-chain CPs (SCCPs and MCCPs) at an environmentally relevant concentration of 10 mg/L for 7 days, followed by a 7-day elimination period. Results indicated that CPs could transfer into the head after oral consumption and SCCPs and MCCPs exhibited clear bioaccumulation trends: midgut > hindgut > head. An evaluation of congener group distribution patterns demonstrated that the dominant congener groups in all target tissues were C11-13Cl7-8 and C14Cl7-8 for SCCPs and MCCPs, respectively, consistent with the treated CP standards. In honeybees, a significant negative relationship was observed for the log concentration of MCCP congener groups and their logâ¯KOW, but not with their logâ¯KOA. Conversely, no such correlation was found for SCCPs. These findings suggest that honeybees have a high potential to bioaccumulate MCCPs, particularly those with a low logâ¯KOW, and exhibit weak selectivity for SCCPs.
Assuntos
Parafina , Animais , Abelhas , Parafina/metabolismo , Hidrocarbonetos Clorados/metabolismo , Administração OralRESUMO
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.
Assuntos
Mieloma Múltiplo , Neutropenia , Humanos , Mieloma Múltiplo/patologia , Talidomida , Dexametasona , Recidiva Local de Neoplasia/patologia , Neutropenia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders. Mounting studies have suggested an involvement of angiogenesis signaling in NHLs progression and resistance to treatment. In this study, we investigated the cytotoxicity of CS2164, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2 and Aurora B in NHL cells. By in vitro culture system and in vivo xenograft model, we found that CS2164 significantly inhibited cell growth and abolished clonogenicity in NHL cells in a dose- and time-dependent manner. Meanwhile, CS2164 significantly induced NHL cells apoptosis and cell cycle arrest in G0/G1 phase. Moreover, CS2164 suppressed NHL cells growth and progression in an in vivo xenograft model. Mechanistically, CS2164-induced cytotoxicity was closely associated with inhibition of VEGFR2 and Aurora B as well as their downstream signaling cascades, including P38, ERK and H3 pathways. In conclusion, CS2164 exerts its cytotoxic effect via inhibition of proliferation and induction of apoptosis by modulating VEGFR2 and Aurora B signaling pathway, supporting a potential role for CS2164 in the treatment of NHLs.