MR imaging of the neonatal brain at 3 Tesla

3 Telsa MR scanners are now becoming more widely available and 3 Telsa is likely to become the filed strength of choice for clinical imaging of the brain. The neonatal brain can be safely and successfully imaged at 3 Telsa. The improved signal to noise afforded by a higher field strength may be used to improve image quality or shorten acquisition times. This may be exploited for conventional T1 and T2 weighted imaging and also for advanced techniques such as diffusion tensor imaging, angiography and functional magnetic resonance studies.     

Combination therapy with interleukin-6 receptor superantagonist Sant7 and dexamethasone induces antitumor effects in a novel SCID-hu In vivo model of human multiple myeloma.

Interleukin-6 (IL-6) protects multiple myeloma cells against apoptosis induced by glucocorticoids. Here, we investigated whether inhibition of the IL-6 signaling pathway by the IL-6 receptor superantagonist Sant7 enhances the in vivo antitumor effects of dexamethasone on the IL-6-dependent multiple myeloma cell line INA-6. For this purpose, we used a novel murine model of human multiple myeloma in which IL-6-dependent INA-6 multiple myeloma cells were directly injected into human bone marrow implants in severe combined immunodeficient (SCID) mice (SCID-hu). The effect of in vivo drug treatments on multiple myeloma cell growth was monitored by serial determinations of serum levels of soluble IL-6 receptor (shuIL-6R), which is released by INA-6 cells and served as a marker of tumor growth. In SCID-hu mice engrafted with INA-6 cells, treatment with either Sant7 or dexamethasone alone did not induce significant reduction in serum shuIL-6R levels. In contrast, the combination of Sant7 with dexamethasone resulted in a synergistic reduction in serum shuIL-6R levels after 6 consecutive days of treatment. Gene expression profiling of INA-6 cells showed down-regulation of proliferation/maintenance and cell cycle control genes, as well as up-regulation of apoptotic genes in multiple myeloma cells triggered by Sant7 and dexamethasone combination. In vitro colony assays showed inhibition of myeloid and erythroid colonies from normal human CD34(+) progenitors in response to dexamethasone, whereas Sant7 neither inhibited colony growth nor potentiated the inhibitory effect of dexamethasone. Taken together, these results indicate that inhibition of IL-6 signaling by Sant7 significantly potentiates the therapeutic action of dexamethasone against multiple myeloma cells, providing the preclinical rationale for clinical trials of Sant7 in combination with dexamethasone to improve patient outcome in multiple myeloma.     

Why STAN might not be dead

Recently, a meta-analysis, including 26?526 laboring vertex singletons at term, summarized all available level-1 data from six high-quality randomized clinical trials (RCTs) on the use of ST analysis (STAN) during labor as an adjunct to conventional intrapartum fetal heart rate monitoring. The meta-analysis showed that STAN did not improve perinatal outcomes or decrease cesarean deliveries. Nonetheless, there are still reasons to believe STAN may have a role in the future research on intrapartum fetal monitoring. Out of six trials included in the meta-analysis, two included all cephalic singletons in labor, and four enrolled only high-risk pregnant women. This combination of both low- and high-risk populations may have distorted the potential impact of STAN. The test for heterogeneity between both subgroups was found to be statistically significant, indicating that the effect of STAN was different in high-risk women compared to a combination of both low- and high-risk women. Furthermore, the classifications of the fetal heart rate patterns used in the included randomized trials were different. Last but not least, despite?>26?000 women with singleton gestations were included in the meta-analysis, the evidence still suffers from a lack of power, especially for subgroup analyses. In summary, while the level-1 data so far indicate overall no perinatal benefit of adding STAN to conventional intrapartum fetal heart rate monitoring for the outcomes most of interest, several issues point to the fact that more research is needed before the STAN technology can be deemed of no value for fetal monitoring in labor.     

Red grape (Vitis vinifera L.) flavonoids down‐regulate collagen type III expression after UV‐A in primary human dermal blood endothelial cells

Red grape (Vitis vinifera L.) flavonoids including flavan‐3‐ols (eg, catechin and epicatechin), flavonols (eg, quercetin) and anthocyanins (eg, malvidin) exert anti‐inflammatory and antioxidant activities. In the skin they also have a photoprotective action, and their effects have been extensively investigated in keratinocytes, melanocytes and fibroblasts. Despite their known effects also on blood vasculature, little is known on their activities on human dermal blood endothelial cells (HDBECs), which are critically involved in skin homeostasis as well as in the pathogenesis of neoplastic and inflammatory skin diseases. We sought to study the biological effects of selected red grape flavonoids in preventing the consequences of ultraviolet (UV)‐A irradiation in vitro. Our results show that red grape flavonoids prevent UV‐A‐induced sICAM‐1 release in HDBECs, suggesting that this cell type could represent an additional target of the anti‐inflammatory activity of flavonoids. In addition, flavonoids effectively inhibited UV‐A‐induced synthesis of collagen type III at both RNA and protein level, indicating that dermal blood microvasculature could be actively involved in ECM remodelling as a consequence of skin photo‐ageing, and that this can be prevented by red grape flavonoids.     

Mutational landscape of patients with acute promyelocytic leukemia at diagnosis and relapse

Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile.