The activity state of factor VII in plasma: two pathways for the cold promoted activation of factor VII

The apparent amount of factor VII as determined in a one-stage test depends on the type of thromboplastin used: bovine thromboplastin only reacts with human factor VIIa whereas human thromboplastin interacts with unactivated human factor VII as well. Therefore the ratio factor VII activity as measured with bovine thromboplastin divided by the factor VII activity as assessed with human thromboplastin reflects the state of activation of factor VII in plasma. This approach was used to study the process of cold promoted factor VII activation and the involvement of different clotting factors therein. It could be shown that cold promoted activation does not occur in the absence of factors II and XII and is reduced for about 50% in factor IX deficient plasma. The other coagulation factors have a minor influence on the process. The results indicate that the cold promoted factor VII activation is the result of activation by both activated contact products and thrombin.     

Astrocyte lipid metabolism is critical for synapse development and function in vivo

The brain is considered to be autonomous in lipid synthesis with astrocytes producing lipids far more efficiently than neurons. Accordingly, it is generally assumed that astrocyte‐derived lipids are taken up by neurons to support synapse formation and function. Initial confirmation of this assumption has been obtained in cell cultures, but whether astrocyte‐derived lipids support synapses in vivo is not known. Here, we address this issue and determined the role of astrocyte lipid metabolism in hippocampal synapse formation and function in vivo. Hippocampal protein expression for the sterol regulatory element‐binding protein (SREBP) and its target gene fatty acid synthase (Fasn) was found in astrocytes but not in neurons. Diminishing SREBP activity in astrocytes using mice in which the SREBP cleavage‐activating protein (SCAP) was deleted from GFAP‐expressing cells resulted in decreased cholesterol and phospholipid secretion by astrocytes. Interestingly, SCAP mutant mice showed more immature synapses, lower presynaptic protein SNAP‐25 levels as well as reduced numbers of synaptic vesicles, indicating impaired development of the presynaptic terminal. Accordingly, hippocampal short‐term and long‐term synaptic plasticity were defective in mutant mice. These findings establish a critical role for astrocyte lipid metabolism in presynaptic terminal development and function in vivo. GLIA 2017;65:670–682     

Influence of aminoglutethimide on plasma levels of medroxyprogesterone acetate: its correlation with serum cortisol

Postmenopausal patients with metastatic breast cancer were treated with aminoglutethimide (AG) and high-dose medroxyprogesterone acetate (MPA). Studying the interaction between the two drugs as far as plasma MPA and cortisol levels are concerned we observed a 50% decrease of plasma MPA levels after the addition of AG (P less than 0.005). With large interindividual differences in plasma MPA levels, a significant correlation with serum cortisol levels was found (P less than 0.001). It can be concluded that AG leads to a lowering of plasma MPA levels to such an extent that its adrenal suppressive effect may be diminished or even abrogated. In future trials of MPA with or without AG correlations between plasma MPA levels, serum cortisol levels and treatment response should be taken into account.     

Phase II study of edatrexate in chemotherapy-naive patients with metastatic breast cancer.

A phase II trial of the new antifolate edatrexate (10-ethyl-10-deaza-aminopterin) was performed in thirty-eight patients with metastatic breast cancer who had never received chemotherapy. Edatrexate was administered as a weekly intravenous bolus injection at a dose of 80 mg/m2. Sites of metastases included visceral (31%), soft tissue/lymph node/bone (51%), and bone only (18%). Thirty-two patients were evaluable for response; there were 3 complete responses (CR) and 8 partial responses (PR), yielding a response rate (CR plus PR) of 34% (95% confidence limits, 17.9% to 50.9%). Responses were seen in soft tissue metastases, in visceral metastases (liver, lung) and in one patient with bone metastases. Median duration of response was 30 weeks (range 12-66 weeks). Substantial toxicity was observed. The dose-limiting toxicities were mucositis, myelo-suppression and skin toxicity. The general toxicity profile was similar to that usually reported for methotrexate, but mucositis and skin toxicity were more pronounced. Edatrexate appears to be an active drug in the treatment of chemotherapy-native patients with metastatic breast cancer.     

Weekly docetaxel in metastatic breast cancer patients: no superior benefits compared to three-weekly docetaxel

Background

In anthracycline-pretreated metastatic breast cancer (MBC) patients, it is unknown whether weekly single-agent docetaxel is preferable to 3-weekly docetaxel regarding its toxicity and efficacy profile.

Patients and methods

In this multicenter, randomised, open-label phase III trial, 162 patients were randomised to weekly docetaxel (group A) or 3-weekly docetaxel (group B). The primary end-point was tolerability; secondary end-points were efficacy and quality of life (QoL).

Results

Group A (weekly docetaxel, n = 79) experienced less haematological toxicity, with just 1.3% versus 16.9% febrile neutropenia in group B (3-weekly docetaxel, n = 77) (p = 0.001). Not this difference, but fatigue and general malaise foremost led to more patient withdrawals in group A (24 versus 12 patients, p = 0.032), less patients completing treatment (29 versus 43 patients, p = 0.014) and reduced dose-intensity (15.6 versus 26 mg/m²/week, 58% versus 70% of projected dose, p = 0.017). As a result, 3-weekly docetaxel was related to better overall survival in multivariate analysis (hazard ratio 0.70, p = 0.036), although in univariate analysis efficacy was similar in both groups. Reported QoL was similar in both groups, but less effective treatment with more general toxicity led to less completed QoL forms in group A (65.4% versus 50%, p=0.049).

Conclusion

Weekly docetaxel is less well tolerated than a 3-weekly schedule, due to more non-haematological toxicity, despite less febrile neutropenia. Also, no efficacy benefits can be demonstrated for weekly docetaxel, which may even be inferior based on multivariate analysis. Therefore, a 3-weekly schedule should be preferred in the setting of MBC.     

Astrocytes are central in the pathomechanisms of vanishing white matter

Vanishing white matter (VWM) is a fatal leukodystrophy that is caused by mutations in genes encoding subunits of eukaryotic translation initiation factor 2B (eIF2B). Disease onset and severity are codetermined by genotype. White matter astrocytes and oligodendrocytes are almost exclusively affected; however, the mechanisms of VWM development remain unclear. Here, we used VWM mouse models, patients’ tissue, and cell cultures to investigate whether astrocytes or oligodendrocytes are the primary affected cell type. We generated 2 mouse models with mutations (Eif2b5^{Arg191His/Arg191His} and Eif2b4^{Arg484Trp/Arg484Trp}) that cause severe VWM in humans and then crossed these strains to develop mice with various mutation combinations. Phenotypic severity was highly variable and dependent on genotype, reproducing the clinical spectrum of human VWM. In all mutant strains, impaired maturation of white matter astrocytes preceded onset and paralleled disease severity and progression. Bergmann glia and retinal Müller cells, nonforebrain astrocytes that have not been associated with VWM, were also affected, and involvement of these cells was confirmed in VWM patients. In coculture, VWM astrocytes secreted factors that inhibited oligodendrocyte maturation, whereas WT astrocytes allowed normal maturation of VWM oligodendrocytes. These studies demonstrate that astrocytes are central in VWM pathomechanisms and constitute potential therapeutic targets. Importantly, astrocytes should also be considered in the pathophysiology of other white matter disorders.     

The involvement of astrocytes in early-life adversity induced programming of the brain

Early-life adversity (ELA) in the form of stress, inflammation, or malnutrition, can increase the risk of developing psychopathology or cognitive problems in adulthood. The neurobiological substrates underlying this process remain unclear. While neuronal dysfunction and microglial contribution have been studied in this context, only recently the role of astrocytes in early-life programming of the brain has been appreciated. Astrocytes serve many basic roles for brain functioning (e.g., synaptogenesis, glutamate recycling), and are unique in their capacity of sensing and integrating environmental signals, as they are the first cells to encounter signals from the blood, including hormonal changes (e.g., glucocorticoids), immune signals, and nutritional information. Integration of these signals is especially important during early development, and therefore we propose that astrocytes contribute to ELA induced changes in the brain by sensing and integrating environmental signals and by modulating neuronal development and function. Studies in rodents have already shown that ELA can impact astrocytes on the short and long term, however, a critical review of these results is currently lacking. Here, we will discuss the developmental trajectory of astrocytes, their ability to integrate stress, immune, and nutritional signals from the early environment, and we will review how different types of early adversity impact astrocytes.     

Activation of factor VII in patients with carcinoma of the prostate. A preliminary report

A preliminary report suggests a correlation between metastatic prostate cancer and increased plasma factor VIIa levels. Prostate cancer without metastases and prostate hypertrophy showed no clear pattern in factor VIIa. Further investigations concerning the relation between metastatic cancer and clotting factors are in progress.