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.

Pediatric heart transplantation requires lifelong immune suppression and may require thymectomy, both of which alter T-cell repertoires. We hypothesized that atopic and autoimmune diseases are more common in pediatric heart transplant patients than the general population, and that transplantation in early childhood increases the risk of development or worsening of atopic or autoimmune disease. A cross-sectional single-center study including 21 heart transplant patients aged ≤18 years was conducted. Data collected included age at transplant, induction, thymectomy, and development and severity of atopic or autoimmune disease. A majority (67%) reported having any atopic disease post-transplant, all of whom reported onset or worsening post-transplantation. Thymectomized patients were significantly more likely to have asthma (P = 0.018) and report asthma worsening post-transplant (P = 0.045). Patients with worsening of asthma post-transplant were transplanted at a significantly younger age (P = 0.040). ABO incompatible and ABO compatible recipients presented similarly. Anemia was common (38%) but not always clearly of autoimmune origin. Atopic diseases are common in children following heart transplantation: Compared to the general population, there is a higher prevalence of eczema (43% vs 11%) and asthma (33% vs 9%). Both thymectomy and younger age at transplant are associated with atopic disorders, possibly due to altered T-cell repertoires.

A crucial mode of action of trastuzumab is the labeling of HER2-positive (HER2+) tumor cells for the eradication by natural killer (NK) cells, a process called antibody-dependent cellular cytotoxicity (ADCC). However, despite widespread HER2 expression among cancer entities, only a fraction, with robust HER2 overexpression, benefits from trastuzumab therapy. ADCC requires both sufficient lymphocytic infiltration and close binding of the immune cells to the antibody-tagged tumor cells. We hypothesized that the chemokine CX3CL1 could improve both processes, as it is synthesized as a membrane-bound, adhesive form that is eventually cleaved into a soluble, chemotactic protein. Here, we show that CX3CL1 overexpression is a positive prognostic marker in breast cancer. CX3CL1 overexpression attracted tumor-suppressive lymphocytes, including NK cells, and inhibited tumor growth and lung metastasis in the syngeneic 4T1 breast cancer mouse model. In HER2+ SKBR3, MDA-MB-453, and HT-29 tumor cells, CX3CL1 overexpression increased NK cell–mediated cytotoxicity in vitro and acted synergistically with trastuzumab. Even though CX3CL1 did not further improve trastuzumab efficacy in vivo in the trastuzumab-sensitive MDA-MB-453 model, it compensated for NK-cell depletion and prolonged survival. In the HER2 low–expressing HT-29 model, however, CX3CL1 overexpression not only prolonged survival time but also overcame trastuzumab resistance in a partly NK cell–dependent manner. Taken together, these findings identify CX3CL1 as a feasible pharmacologic target to enable trastuzumab therapy in HER2 low–expressing cancers and render it a potential predictive biomarker to determine therapy responders.

Pediatric heart transplantation requires lifelong immune suppression and may require thymectomy, both of which alter T‐cell repertoires. We hypothesized that atopic and autoimmune diseases are more common in pediatric heart transplant patients than the general population, and that transplantation in early childhood increases the risk of development or worsening of atopic or autoimmune disease. A cross‐sectional single‐center study including 21 heart transplant patients aged ≤18 years was conducted. Data collected included age at transplant, induction, thymectomy, and development and severity of atopic or autoimmune disease. A majority (67%) reported having any atopic disease post‐transplant, all of whom reported onset or worsening post‐transplantation. Thymectomized patients were significantly more likely to have asthma (P = 0.018) and report asthma worsening post‐transplant (P = 0.045). Patients with worsening of asthma post‐transplant were transplanted at a significantly younger age (P = 0.040). ABO incompatible and ABO compatible recipients presented similarly. Anemia was common (38%) but not always clearly of autoimmune origin. Atopic diseases are common in children following heart transplantation: Compared to the general population, there is a higher prevalence of eczema (43% vs 11%) and asthma (33% vs 9%). Both thymectomy and younger age at transplant are associated with atopic disorders, possibly due to altered T‐cell repertoires.