Ultrafiltration and PD are highly effective in removing proinflammatory cytokines. Impaired kidney function was associated with proinflammatory IL-serum concentrations. Thus, we raise the hypothesis that glomerular-filtered proinflammatory ILs damage the proximal tubular cells of the kidney in newborns and infants, thus contributing to post-operative renal dysfunction. Conversely, we conclude that removing proinflammatory ILs by ultrafiltration and PD acts renoprotectively. A future prospective randomised study could demonstrate whether this can indeed improve clinical outcome.
Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the brain microenvironment is less understood. Therefore we aimed to quantify the PI3K pathway activity in breast cancer brain metastasis and investigate the effects of PI3K inhibition on the central nervous system (CNS) microenvironment. First, to systematically quantify the PI3K pathway activity in breast cancer brain metastases, we performed a prospective biomarker study using a reverse phase protein array (RPPA). The majority, namely 30 out of 48 (62.5%) brain metastatic tissues examined, revealed high PI3K signaling activity that was associated with a median overall survival (OS) of 9.41 months, while that of patients, whose brain metastases showed only moderate or low PI3K activity, amounted to only 1.93 and 6.71 months, respectively. Second, we identified PI3K as a master regulator of metastasis‐promoting macrophages/microglia during CNS colonization; and treatment with buparlisib (BKM120), a pan‐PI3K Class I inhibitor with a good blood‐brain‐barrier penetrance, reduced their metastasis‐promoting features. In conclusion, PI3K signaling is active in the majority of breast cancer brain metastases. Since PI3K inhibition does not only affect the metastatic cells but also re‐educates the metastasis‐promoting macrophages/microglia, PI3K inhibition may hold considerable promise in the treatment of brain metastasis and the respective microenvironment.
In patients after congenital heart surgery, urine NGAL indicates the damaging force of cardiopulmonary bypass and serum Cystatin C is a valuable predictive biomarker for resulting acute kidney injury.
Background
Response to immune checkpoint blockade (ICB) in ovarian cancer remains disappointing. Several studies have identified the chemokine CXCL9 as a robust prognosticator of improved survival in ovarian cancer and a characteristic of the immunoreactive subtype, which predicts ICB response. However, the function of CXCL9 in ovarian cancer has been poorly studied.
Methods
Impact of Cxcl9 overexpression in the murine ID8-Trp53−/− and ID8-Trp53−/–Brca2−/− ovarian cancer models on survival, cellular immune composition, PD-L1 expression and anti-PD-L1 therapy. CXCL9 expression analysis in ovarian cancer subtypes and correlation to reported ICB response.
Results
CXCL9 overexpression resulted in T-cell accumulation, delayed ascites formation and improved survival, which was dependent on adaptive immune function. In the ICB-resistant mouse model, the chemokine was sufficient to enable a successful anti-PD-L1 therapy. In contrast, these effects were abrogated in Brca2-deficient tumours, most likely due to an already high intrinsic chemokine expression. Finally, in ovarian cancer patients, the clear-cell subtype, known to respond best to ICB, displayed a significantly higher proportion of CXCL9high tumours than the other subtypes.
Conclusions
CXCL9 is a driver of successful ICB in preclinical ovarian cancer. Besides being a feasible predictive biomarker, CXCL9-inducing agents thus represent attractive combination partners to improve ICB in this cancer entity.
Heterometallic NHC complexes have been selectively prepared at room temperature directly from an azolium salt in a two-step procedure. In the unsymmetrically substituted bis(1,2,4-triazolium) ligand precursor, one of the m-xylylene-bridged triazolium units features an unprotected o-thiophenol substituent. This renders possible a selective deprotonation and in situ monopalladation at the NHC−thiolato unit. The obtained palladium(II) complex possesses two pendant triazolium units as vacant binding sites. After a second deprotonation/metalation step, a heterodinuclear palladium(II) gold(I) complex and a heterotrinuclear palladium(II) dicopper(I) complex were obtained. In the latter, two metal centers are connected via a thiolato bridge.
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