Topological Characteristics of Harmonic Quasiconformal Unit Disk Automorphisms in the Uniform Topology

We study the class $HQ(\mathbb{D})$, the set of harmonic quasiconformal automorphisms of the unit disk $\mathbb{D}$ in the complex plane, endowed with the topology of uniform convergence. Several important topological properties of this space of mappings are investigated, such as separability, compactness, path--connectedness and completeness

Low Vitamin D Status Predicts Poor Clinical Outcome in Advanced Melanoma Treated With Immune Checkpoint or BRAF/MEK Inhibitors: A Prospective Non-Interventional Side-by-Side Analysis

In melanoma and other malignancies, low vitamin D status is associated with increased risk and poor prognosis. However, there are limited data of the impact of 25(OH)D serum concentration (s.c.) on clinical outcome in advanced melanoma. We tested the hypothesis that vitamin D status is predictive of efficacy and safety in patients treated for metastasized melanoma with B-rapidly accelerated fibrosarcoma (BRAF), mitogen-activated protein kinase kinase (MEK), cytotoxic T lymphocyte-associated protein-4 (CTLA-4), and/or programmed cell death protein-1 (PD-1) inhibitors. Severe vitamin D deficiency [defined as 25(OH)D s.c. <10 ng/ml] was associated with markedly reduced overall (OS) and progress-free (PFS) survival, with increased tumor load [TL; measured as s.c. of S100 protein or lactate dehydrogenase (LDH)], and with a trend for higher frequency of adverse events (AEs). An increase in average 25(OH)D s.c. of 1 ng/ml was associated with a 3.9% reduced risk for progressive disease [hazard ratio (HR) = 0.961, p = 0.044], with a reduction of LDH s.c. of 3.86 U/l (p = 0.034, indicating a reduction of TL), and with a trend for reduced frequency of AEs (AE ratio -0.005; p = 0.295). Patients with average 25(OH)D s.c. ≥10 ng/ml and BRAF-mutant melanoma showed a trend for a higher frequency of AEs as compared to individuals with BRAF wild-type melanomas. Our data indicate that vitamin D deficiency is associated with poor clinical outcome in patients treated for metastasized melanoma with BRAF/MEK inhibitors or immunotherapy. Although it needs to be proven in future interventional trials whether optimizing serum 25(OH)D improves clinical outcome in these patients, we recommend that 25(OH)D s.c. should be analyzed and vitamin D deficiency treated in all patients with advanced melanoma

Entropically-driven binding of mithramycin in the minor groove of C/G-rich DNA sequences

Final full-text version available at: http://dx.doi.org/10.1093/nar/gkm037.-- Supplementary Data is available.The antitumour antibiotic mithramycin A (MTA) is a DNA minor-groove binding ligand. It binds to C/G-rich tracts as a dimer that forms in the presence of divalent cations such as Mg2+. Differential scanning calorimetry, UV thermal denaturation, isothermal titration calorimetry and competition dialysis were used, together with computations of the hydrophobic free energy of binding, to determine the thermodynamic profile of MTA binding to DNA. The results were compared to those obtained in parallel using the structurally related mithramycin SK (MSK). The binding of MTA to salmon testes DNA determined by UV melting studies (Kobs = 1.2 (±0.3) x 10^5 M–1) is tighter than that of MSK (2.9 (±1.0) x 10^4 M–1) at 25°C. Competition dialysis studies showed a tighter MTA binding to both salmon testes DNA (42% C + G) and Micrococcus lysodeikticus DNA (72% C + G). The thermodynamic analysis of binding data at 25°C shows that the binding of MTA and MSK to DNA is entropically driven, dominated by the hydrophobic transfer of the antibiotics from solution to the DNA-binding site. Direct molecular recognition between MTA or MSK and DNA through hydrogen bonding and van der Waals contacts may also contribute significantly to complex formation.Supported by a grant from the Spanish Ministry of Education and Science (SAF2005-00551) and the FEDER program of the European Community. This work was carried out within the framework of the Centre de Referencia en Biotecnologia of the Generalitat de Catalunya. Funding to pay the Open Access publication charge was provided by the Ministry of Education and Science and CSIC (Spain).Peer reviewe

Oxazole-Bridged Combretastatin A-4 Derivatives with Tethered Hydroxamic Acids: Structure-Activity Relations of New Inhibitors of HDAC and/or Tubulin Function

New inhibitors of tubulin polymerization and/or histone deacetylase (HDAC) activity were synthesized by attaching alkyl tethered hydroxamic acid appendages of varying length to oxazole-bridged combretastatin A-4 analogous caps. While their antiproliferative and microtubule disrupting effect was most pronounced for derivatives with short spacers, HDAC inhibition was strongest for those with longer spacers. These findings were further supported by computational methods such as structure-based docking experiments exploring the target interactions of the derivatives with varying linkers. For instance, compounds featuring short four-atom spacers between cap and hydroxamic acid inhibited the growth of various cancer cell lines and human endothelial hybrid cells with IC50 values in the low nanomolar range. In line with their ability to inhibit the microtubule assembly, four- and five-atom spacered hydroxamic acids caused an accumulation of 518A2 melanoma cells in G2/M phase, whereas a compound featuring a six-atom spacer and performing best in HDAC inhibition, induced a G1 arrest in these cells. All these beneficial anticancer activities together with their selectivity for cancer cells over non-malignant cells, point out the great potential of these novel pleiotropic HDAC and tubulin inhibitors as drug candidates for cancer therapy

Response and long-term control of bone metastases after peptide receptor radionuclide therapy with (177)Lu-octreotate

Peptide receptor radionuclide therapy (PRRT) is an efficient treatment for gastroenteropancreatic neuroendocrine tumors (GEP NETs), with outstanding overall response rates and survival. However, little is known about the particular efficacy regarding bone metastasis (BM)