Impact of cardiac fibrosis and collagens on right ventricular failure and acute kidney injury in patients after continuous-flow left ventricular assist devices

 Open in a separate windowOBJECTIVESWe aim to investigate the impact of cardiac fibrosis and collagens on right ventricular failure (RVF) and acute kidney injury (AKI) in patients receiving continuous flow left ventricular assist devices.METHODSHeart tissues from 34 patients were obtained from continuous flow left ventricular assist device insertion sites and corresponding clinical data were collected. The participants were divided into 2 groups according to the extent of the cardiac fibrosis or collagens.RESULTSOverall, 18 patients developed RVF with 14 receiving right ventricular assist device (RVAD), and 22 patients developed AKI with 12 needing new-onset renal replacement therapy. Higher collagen I (Col1) was significantly associated with increased incidences of RVF (76.5% vs 29.4%, P = 0.015), RVAD support (64.7% vs 17.6%, P = 0.013) and stage 3 AKI (58.8% vs 17.6%, P = 0.032), and patients with higher Col1 were more prone to renal replacement therapy (52.9% vs 17.6%, P = 0.071). Receiver operating characteristic curves showed that Col1 had good predictive effects on RVF [area under the curve (AUC) = 0.806, P = 0.002], RVAD support (AUC = 0.789, P = 0.005), stage 3 AKI (AUC = 0.740, P = 0.020) and renal replacement therapy (AUC = 0.731, P = 0.028) after continuous-flow left ventricular assist device. Moreover, patients with higher Col1 had significantly longer postoperative duration of mechanical ventilation, duration of intensive care unit stay and hospital length of stay (all P < 0.05). Cardiac fibrosis, collagen III (Col3) and Col1/Col3 shared similar results or trends with Col1.CONCLUSIONSCardiac fibrosis and related collagens in the apical left ventricular tissue are associated with increased risks of RVF, RVAD use and worse renal function. Further study is warranted owing to the small sample size.     

Biomarker profile for prediction of response to SMAC mimetic monotherapy in pediatric precursor B-cell acute lymphoblastic leukemia

Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) targeting inhibitor of apoptosis proteins (IAPs) activate cell death pathways, and are currently being evaluated in clinical trials. Their successful therapeutic implementation requires upfront identification of patients who could benefit from a SM-based treatment but biomarkers for SM sensitivity have not yet been described. Here, we analyzed the intrinsic activity of two monovalent (AT406 and LCL161) and two bivalent (Birinapant and BV6) SMs on unselected patient-derived pediatric precursor B-cell acute lymphoblastic leukemia (BCP-ALL) identifying a subset of patient samples to be particularly sensitive to SM-induced cell death. This subset was defined by a characteristic gene expression signature with 127 differentially regulated genes, amongst them TNFRSF1A encoding TNFR1, and a critical role of TNFR1 in SM-induced cell death in sensitive BCP-ALL was confirmed on the functional level. Interestingly, samples with intermediate or low sensitivity to SMs were sensitized to SM-induced cell death by inhibition of caspases using zVAD.fmk or Emricasan, a pan-caspase inhibitor in clinical trials. When we compared our expression data to published data sets, we identified an overlap of four genes to be commonly differentially regulated in SM-sensitive BCP-ALL, that is, TSPAN7, DIPK1C, MTX2 and, again, TNFRSF1A. Functional testing revealed that this set of genes identified samples with high sensitivity to SM treatment. In summary, our data suggest using this gene signature as biomarker predicting response to SM treatment and point to the development of new combinatorial treatments consisting of SMs and pan-caspase inhibitors for a successful clinical implementation of SMs in treatment of BCP-ALL.     

Chemosensitization of glioblastoma cells by the histone deacetylase inhibitor MS275

Glioblastoma is the most common primary brain tumor with a dismal prognosis, highlighting the need for novel treatment strategies. Here, we provide the first evidence that the histone deacetylase inhibitor, MS275, sensitizes glioblastoma cells for chemotherapy-induced apoptosis. Pretreatment of glioblastoma cells with MS275 causes acetylation of histone H3 protein and significantly enhances doxorubicin-induced apoptosis. Calculation of combination index showed that MS275 and doxorubicin acted in a synergistic manner to trigger apoptosis. Furthermore, pre-exposure to MS275 significantly increases apoptosis in response to temozolomide, etoposide, and cisplatin. In contrast, treatment with MS275 before the addition of vincristine and taxol significantly reduces the induction of apoptosis. Analysis of cell cycle alterations showed that treatment with MS275 triggers G1 cell cycle arrest, which in turn renders cells less sensitive to the cytotoxic effects of mitotic inhibitors, such as vincristine and taxol. Thus, these findings show for the first time that the histone deacetylase inhibitor, MS275, represents a promising strategy to prime glioblastoma cells for chemotherapy-induced apoptosis in a drug-specific manner.     

Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101, a CD95-Fc fusion protein, in healthy volunteers and two glioma patients

APG101 is a glycosylated fusion protein consisting of the extracellular domain of human CD95 (APO-1/Fas) and the Fc domain of human IgG1. Administration of APG101 blocks the interaction between CD95 and its cognate ligand CD95L, thereby inhibiting various pathways involved in e.g. proliferation, migration, differentiation and apoptosis induction. The safety and tolerability of ascending single doses of intravenously applied APG101 was examined in a randomized, double-blind, placebo-controlled, mono-centre "first in man" dose escalation study in 34 healthy male volunteers. Pharmacokinetics and pharmacodynamics were also assessed. The maximum serum concentration of 460 μg/ml was achieved following 1h infusion of the highest dose of 20 mg/kg. The systemic clearance was low (0.4 to 0.5 ml/hkg). Mean terminal elimination half-life was 12 to 15 days. Two patients suffering from malignant glioma received APG101 intravenously under compassionate use conditions. They received doses ranging from 5mg to 600 mg APG101. No adverse events and no clinical significant changes in laboratory parameters related to APG101 were reported. The presence of anti-drug-antibodies (ADA) was investigated and revealed no detectable levels of ADA. Overall, single ascending doses of APG101 up to 20 mg/kgbody weight (bw) administered as infusion over 1h were considered as safe and well tolerated in healthy volunteers. After the application of multiple doses of 400 mg in two glioma patients, steady state for APG101 seemed to be reached. These results support further clinical evaluation of APG101 at a dose of 400 mg per week in glioblastoma patients.     

Requirement of Nuclear Factor ��B for Smac Mimetic-Mediated Sensitization of Pancreatic Carcinoma Cells for Gemcitabine-Induced Apoptosis

Defects in apoptosis contribute to treatment resistance and poor outcome of pancreatic cancer, calling for novel therapeutic strategies. Here, we provide the first evidence that nuclear factor (NF) κB is required for Smac mimetic-mediated sensitization of pancreatic carcinoma cells for gemcitabine-induced apoptosis. The Smac mimetic BV6 cooperates with gemcitabine to reduce cell viability and to induce apoptosis. In addition, BV6 significantly enhances the cytotoxicity of several anticancer drugs against pancreatic carcinoma cells, including doxorubicin, cisplatin, and 5-fluorouracil. Molecular studies reveal that BV6 stimulates NF-κB activation, which is further increased in the presence of gemcitabine. Importantly, inhibition of NF-κB by overexpression of the dominant-negative IκBα superrepressor significantly decreases BV6- and gemcitabine-induced apoptosis, demonstrating that NF-κB exerts a proapoptotic function in this model of apoptosis. In support of this notion, inhibition of tumor necrosis factor α (TNFα) by the TNFα blocking antibody Enbrel reduces BV6- and gemcitabine-induced activation of caspase 8 and 3, loss of mitochondrial membrane potential, and apoptosis. By demonstrating that BV6 and gemcitabine trigger a NF-κB-dependent, TNFα-mediated loop to activate apoptosis signaling pathways and caspase-dependent apoptotic cell death, our findings have important implications for the development of Smac mimetic-based combination protocols in the treatment of pancreatic cancer.     

Vulvodynie

Vulvodynia is a complex syndrome of chronic vulvar pain. It is divided into several subtypes: 1. cyclic vulvovaginitis (pain occurs after coitus), 2. vulvar vestibulitis syndrome (pain mainly with intercourse), 3. dysaesthetic vulvodynia (psychosomatic; diagnosis of exclusion), 4. vulvar dermatoses (e.g. pemphigus vulgaris, contact dermatitis). Additional causes have been described in single cases. Though vulvodynia is often accompanied by psychological distress, somatic causes have to be considered in each case.