3-Hydroxiglutaric acid (3-OH-GA) is a disease-specific metabolite that accumulates in tissues and body fluids of patients with Glutaric aciduria type I (GAI) and has been associated with vascular ...abnormalities in these kindreds. Here, we demonstrate that 3-OH-GA also affects the integrity of tumor vessels leading to tumor growth inhibition in a subcutaneous model of human glioblastoma multiforme (GBM). This effect correlated with a marked decrease of VE-Cadherin expression in endothelium of 3-OH-GA-treated tumors. Furthermore, in vitro observations indicated also a direct effect of 3-OH-GA in glioma cells that showed defective mitosis and significant proliferation inhibition. In summary, the GAI-specific metabolite 3-OH-GA significantly inhibited growth of GBM xenografts by affecting the structural integrity of tumor blood vessels and in addition by causing defective mitosis and proliferation inhibition of tumor cells.
Development of drug resistance is an inevitable phenomenon in castration-resistant prostate cancer (CRPC) cells requiring novel therapeutic approaches. In this study, efficacy and toxicity of ...Rhizochalinin (Rhiz) - a novel sphingolipid-like marine compound - was evaluated in prostate cancer models, resistant to currently approved standard therapies. In vitro activity and mechanism of action of Rhiz were examined in the human prostate cancer cell lines PC-3, DU145, LNCaP, 22Rv1, and VCaP. Rhiz significantly reduced cell viability at low micromolar concentrations showing most pronounced effects in enzalutamide and abiraterone resistant AR-V7 positive cells. Caspase-dependent apoptosis, inhibition of pro-survival autophagy, downregulation of AR-V7, PSA and IGF-1 expression as well as inhibition of voltage-gated potassium channels were identified as mechanisms of action. Remarkably, Rhiz re-sensitized AR-V7 positive cells to enzalutamide and increased efficacy of taxanes.In vivo activity and toxicity were evaluated in PC-3 and 22Rv1 NOD SCID mouse xenograft models using i.p. administration. Rhiz significantly reduced growth of PC-3 and 22Rv1 tumor xenografts by 27.0% (p = 0.0156) and 46.8% (p = 0.047) compared with controls with an increased fraction of tumor cells showing apoptosis secondary to Rhiz exposure. In line with the in vitro data, Rhiz was most active in AR-V7 positive xenografts in vivo. In animals, no severe side effects were observed.In conclusion, Rhiz is a promising novel marine-derived compound characterized by a unique combination of anticancer properties. Its further clinical development is of high impact for patients suffering from drug resistant prostate cancer especially those harboring AR-V7 mediated resistance to enzalutamide and abiraterone.
Long interspersed nuclear element-1 (LINE-1, L1) is a retrotransposon which affects the human genome by a variety of mechanisms. While LINE-1 expression is suppressed in the most somatic human cells, ...LINE-1 elements are activated in human cancer. Recently, high accumulation of LINE-1-encoded ORF1p and ORF2p in endothelial cells of mature human blood vessels was described. Here, we demonstrate that LINE-1 de novo retrotransposition events lead to a reduction of endothelial cell proliferation and migration in a porcine aortic endothelial (PAE) cell model. Cell cycle studies show a G0/G1 arrest in PAE cells harboring LINE-1 de novo retrotransposition events. Remarkably, in in situ analysis LINE-1-encoded ORF2p was not detectable in tumor blood vessels of different human organs while vascular endothelial cells of corresponding normal organs strongly expressed LINE-1 ORF2p. Quantitative RT-PCR analysis revealed that LINE-1 de novo retrotransposition influences selectively the expression of some angiogenic factors such as VEGF and Tie-2. Thus, our data suggest that LINE-1 de novo retrotransposition events might suppress angiogenesis and tumor vascularisation by reducing the angiogenic capacity of vascular endothelial cells.
Neuroinflammation is a major component in the progression of neurodegenerative diseases such as dementia, although is not its main initiator. Its been demonstrated that inflammatory activation of ...microglia and astrocytes promotes protein aggregation of amyloid plaques and tau tangles, leading to neuronal death through other mechanisms, such as excitotoxicity. Although many studies investigated the effect of systemic inflammation on the progression of dementia and amyloid plaques in genetic mouse models of Alzheimer's disease, is not clear if systemic inflammation can induce dementia per se.
Methods
90‐day Wistar rats were exposed to chronic inflammatory challenges with intraperitoneal injections of LPS in two doses (500 μg/kg and 250 μg/kg) or saline once a week, for a 16‐week period. Rats were euthanasied 24 h after last LPS injection. Behavioral evaluation was conducted through Open Field (OF) and Object Location Memory‐Test (OLM) for spatial memory assessment. Hippocampal S100B content was measured by ELISA, nuclear Nf‐κB was measured by western blot, and L‐3H glutamate uptake was analyzed.
Results
Both groups receiving LPS presented impaired spatial memory in the 24 h OLM, which is characteristic of hippocampal degeneration in animal models of dementia, while OF shown no locomotor impairment. S100B protein remained unchanged between groups, and glutamate uptake was reduced only in LPS 500 μ/kg group. Nuclear fraction of Nf‐κB was increased in both LPS groups.
Discussion
Here, we demonstrate that chronic peripheral inflammatory stimuli promote cognitive impairment in the absence of other underlying neurodegenerative causes, such as genetic background. Increased Nf‐κB in nucleus indicates hippocampal neuroinflammation, despite LPS challenge being peripheral. Besides, glutamate uptake was reduced in the higher dose of LPS, indicating a possible excitotoxic damage. Conversely, S100B content, which is an important biomolecule in inflammatory signaling, was not affected by LPS.
Support or Funding Information
This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Apoio a Pesquisa do Estado do Rio Grande do Sul (FAPERGS)
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
Requirement of the activation-induced deaminase Arakawa, Hiroshi; Hauschild, Jessica; Buerstedded, Jean-Marie
Science (American Association for the Advancement of Science),
02/2002, Letnik:
295, Številka:
5558
Journal Article
Patients with surgically resected stage III melanoma are at high risk for recurrence. The 5-year survival rate with ipulimumab was 11 percentage points higher than that with placebo (65% vs. 54%), ...but there were substantial immune-related toxic effects.
Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4) to augment antitumor immune responses, was approved by the Food and Drug Administration (FDA) and the European Medicines Agency in 2011 at a dose of 3 mg per kilogram of body weight for the treatment of advanced melanoma.
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On the basis of data from a phase 2 trial that indicated the potential for a dose of 10 mg per kilogram to have higher efficacy than the dose of 0.3 mg or 3 mg per kilogram in patients with advanced melanoma, although at a cost of more . . .
Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced—ie, unresectable or metastatic—melanoma. This criterion, however, ...excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population.
We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18–80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1–12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing.
Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n=56), nivolumab (n=59), or placebo (n=52). As of July 2, 2019, at a median follow-up of 28·4 months (IQR 17·7–36·8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12·4 months (95% CI 5·3–33·3) in the nivolumab group and 6·4 months (3·3–9·6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0·23 (97·5% CI 0·12–0·45; p<0·0001), and for the nivolumab group versus placebo group was 0·56 (0·33–0·94; p=0·011). In the nivolumab plus ipilimumab group, recurrence-free survival at 1 year was 75% (95% CI 61·0–84·9) and at 2 years was 70% (55·1–81·0); in the nivolumab group, 1-year recurrence-free survival was 52% (38·1–63·9) and at 2 years was 42% (28·6–54·5); and in the placebo group, this rate was 32% (19·8–45·3) at 1 year and 14% (5·9–25·7) at 2 years. Treatment-related grade 3–4 adverse events were reported in 71% (95% CI 57–82) of patients in the nivolumab plus ipilimumab group and in 27% (16–40) of those in the nivolumab group. Treatment-related adverse events of any grade led to treatment discontinuation in 34 (62%) of 55 patients in the nivolumab plus ipilimumab group and seven (13%) of 56 in the nivolumab group. Three deaths from adverse events were reported but were considered unrelated to the study treatment.
Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3–4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease.
Bristol-Myers Squibb.
Tebentafusp is a new T cell receptor bispecific fusion protein and the first approved treatment option for human leucocyte antigen-A*02:01 (HLA-A*02:01) metastatic uveal melanoma, with a proven ...benefit in overall survival versus the investigator’s choice. As a first-in-class therapeutic option, this Immune mobilising monoclonal T cell receptor Against Cancer (ImmTAC) is associated with a new adverse event (AE) profile. Based on clinical experience, a national expert group discussed recommendations for tebentafusp treatment, focusing on AE management. Further topics included prerequisites for initiating tebentafusp treatment, appropriate treatment setting, and patient selection criteria. To provide guidance for treating physicians, the resulting recommendations are summarised including a model standard operating procedure for AE management. Patients in good clinical condition and with a low tumour burden are good candidates for tebentafusp treatment, particularly if treated as early as possible after the diagnosis of metastatic disease. The safety profile of tebentafusp is manageable and includes two major pathologies: cytokine release syndrome (CRS) and skin-related events. Postdose monitoring should thus focus on pyrexia and hypotension as the first symptoms of cytokine release. To minimise the risk of hypotension associated with CRS, patients should receive intravenous fluids before starting treatment. The monitoring of liver values is crucial, as patients may experience an increase in transaminases, which can even manifest as tumour lysis syndrome.
•Tebentafusp is a new immune mobilising monoclonal T cell receptor against cancer.•It is approved for therapy of patients with HLA-A*02:01+ metastatic uveal melanoma.•A group of experts provide recommendations on the use of this first-in-class drug.•A model standard operating procedure for adverse event management is provided.
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