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Epigenetic targeting of different cancers by inhibiting particular histone deacetylase (HDAC) isozymes is a promising treatment approach against cancer. Development of locally-implantable molecular inhibitors of HDAC (henceforth called HDACi) promises high tumour site concentration and reduced systemic degradation of the HDACi. Herein, we report the design of such implantable HDACi based on amphiphilic derivatives of hydrophobic amino acids endowed with a hydroxamic acid (hxa)-based zinc-binding residue. The amino acids present in HDACi influenced the HDAC isozyme that could be inhibited most effectively; the l-phenylalanine derivative 4e inhibited the HDAC6 isozyme most potently (IC50 ∼ 88 nM), while the l-isoleucine derivative 4h was most effective against the isozyme HDAC2 (IC50 ∼ 94 nM). We also noticed that the l-Phe derivative 4e was up to 5× more potent towards inhibiting HDAC6 than its optical antipode 4f derived from d-Phe. This was rationalized in terms of the varying extent of penetration of the enantiomeric inhibitors inside the catalytic tunnel of the enzyme. Since the isozymes HDAC6 and HDAC2 are overexpressed in different cancer cells, 4e and 4h elicited selective anticancer activity in different cancer cell lines. Additive therapeutic action of the combination therapy of 4e and 4h was observed on lung cancer cells that overexpress both these isozymes. Further, 4e formed implantable self-assembled hydrogels that achieved sustained and selective killing of cancer cells in the vicinity of implantation.A new heterodimeric crown amphiphile was fabricated, wherein the oxacrown and selencrown ethers provided the desired molecular framework for hydrophilicity and hydrophobicity, respectively. From an integrated perspective, the developed amphiphile possesses features of crown ethers, amines, and selenium-containing species, and its assembly in water can be responsive to diverse chemical effectors-H2O2 and CO2 in a switchable ON/OFF mode to achieve controlled release. It is the first case wherein the applications of cyclic polyethers with different solubilities drives the self-assembly in an aqueous medium.Complex solid solution electrocatalysts (often called high-entropy alloys) present a new catalyst class with highly promising features due to the interplay of multi-element active sites. One hurdle is the limited knowledge about structure-activity correlations needed for targeted catalyst design. We prepared Cr-Mn-Fe-Co-Ni nanoparticles by magnetron sputtering a high entropy Cantor alloy target simultaneously into an ionic liquid library. The synthesized nanoparticles have a narrow size distribution but different sizes (from 1.3 ± 0.1 nm up to 2.6 ± 0.3 nm), different crystallinity (amorphous, face-centered cubic or body-centered cubic) and composition (i.e. high Mn versus low Mn content). The Cr-Mn-Fe-Co-Ni complex solid solution nanoparticles possess an unprecedented intrinsic electrocatalytic activity for the oxygen reduction reaction in alkaline media, some of them even surpassing that of Pt. The highest intrinsic activity was obtained for body-centered cubic nanoparticles with a low Mn and Fe content which were synthesized using the ionic liquid 1-etyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [Emimi][(Tf)2N].Glovebox-AFM-based force curve measurements have been employed to investigate the effect of controlled small amounts of water on the interfacial structure of mica/a pyrrolidinium-based ionic liquid. A close examination reveals that with the increase of water content, the long-range monotonic force, which is beyond the region of the short-range oscillatory structure, switches from van der Waals attraction-dominated force to double layer repulsion-dominated force.We present photocatalytically active, stable polymer-amorphous-MoS3-nanoparticle hybrid structures in aqueous solution. Below 10 nm MoS3 particles in the polymer exhibit an up to 7.5-fold increased photocatalytic activity compared to the neat nanoparticles without any additional photosensitizer. Supramolecular interactions are key in directing the structure formation of the hybrid assembly. The hybrid structures bear potential as novel affordable photocatalysts for solar energy conversion.We propose to overcome oxygen deficiency and light attenuation problems in photodynamic therapy (PDT), by separating photoexcitation and singlet oxygen delivery of the PDT process into two distinct operations to be carried out sequentially, at different locations. We now demonstrate the viability of this approach, using 2-pyridone derivative which yields a relatively stable endoperoxide. The initial storage endoperoxide obtained is transformed enzymatically into a more labile compound when placed in hypoxic cell cultures, and releases singlet oxygen significantly faster. The potential of this approach in advancing PDT beyond its current limits is exciting.We have measured high-resolution time-of-flight (TOF) spectra of methane scattered from an Ir(111) surface at an incident energy of 81 meV. The angular distributions of scattered CH4 reveal the presence of a sharp and intense specular peak in addition to sharp features corresponding to rotationally inelastic diffraction (RID) peaks along the two main symmetry directions of Ir(111). TOF spectra have been recorded at several RID positions for the two high-symmetry directions. The data show that the scattering dynamics of CH4 is more complex than the one reported for H2/D2, where energy losses in TOF correspond to the expected excitation/deexcitation RID energy transitions. TMP195 in vivo For CH4, this is the case only for RID peaks showing up far from the specular peak, whereas those appearing close to the specular position present different behaviors, depending on the incident direction. The results are compared with Ne scattering TOF data, which allows to assess the relevance of multiphonon scattering in the energy-exchange process. Finally, we report experimental evidence of selective adsorption resonances detected with CH4 beams. This will allow characterizing the CH4-metal surface physisorption well by measuring angular distributions with CH4 beams.Directly linked carbazole-based core-modified diporphyrin D2 and fused diporphyrin F2 were synthesized. These diporphyrins showed significant electronic interactions and conjugation allowing for redshifted near infrared (NIR) absorption and small HOMO-LUMO gaps as confirmed by NIR absorption spectroscopy, cyclic voltammetry (CV) measurements, and DFT calculations.KRAS mutations are the most common gain-of-function alterations in lung adenocarcinoma (LADC) in the western countries. Although the different mutations of the KRAS gene have been identified decades ago, the development of drugs targeting the KRAS protein directly have not been successful due to the lack of small molecule binding sites and the extremely high affinity to cellular GTP. Indirect strategies to inhibit KRAS (e.g. inhibitors of farnesyltransferase, prenylation, synthetic lethal partners and KRAS downstream signaling) have so far also failed. In recent times, however several compounds have been developed that target subtype- specific KRAS mutations. Covalent KRAS G12C-specific inhibitors showed the most promising preclinical results. Below, we summarize the predictive and prognostic value of KRAS mutations in LADC as well as the current targeting strategies.Patient suicide is one of the most frequent incidents in healthcare facilities to be reported to the National Observatory of Sentinel Events in Italy. Despite national initiatives, in Tuscany potentially preventable patient suicides still occur in both acute and community care settings. We describe here an aggregated qualitative analysis of 14 patient suicides that took place in public health services between 2017 and 2018. We outline the methodology and results of an improvement action we enacted in the healthcare system that involved reviewing and reinforcing relevant managerial strategies and clinical activities, with the aim of reducing potentially preventable patient suicides.Inhibitors of mitochondrial respiration and ATP synthesis may promote the selective killing of respiration-competent cancer cells that are critical for tumor progression. We previously reported that CADD522, a small molecule inhibitor of the RUNX2 transcription factor, has potential for breast cancer treatment. In the current study, we show that CADD522 inhibits mitochondrial oxidative phosphorylation by decreasing the mitochondrial oxygen consumption rate (OCR) and ATP production in human breast cancer cells in a RUNX2-independent manner. The enzyme activity of mitochondrial ATP synthase was inhibited by CADD522 treatment. Importantly, results from cellular thermal shift assays that detect drug-induced protein stabilization revealed that CADD522 interacts with both α and β subunits of the F1-ATP synthase complex. Differential scanning fluorimetry also demonstrated interaction of α subunits of the F1-ATP synthase to CADD522. These results suggest that CADD522 might target the enzymatic F1 subunits in the ATP synthase complex. CADD522 increased the levels of intracellular reactive oxygen species (ROS), which was prevented by MitoQ, a mitochondria-targeted antioxidant, suggesting that cancer cells exposed to CADD522 may elevate ROS from mitochondria. CADD522-increased mitochondrial ROS levels were enhanced by exogenously added pro-oxidants such as hydrogen peroxide or tert-butyl hydroperoxide. Conversely, CADD522-mediated cell growth inhibition was blocked by N-acetyl-l-cysteine, a general ROS scavenger. Therefore, CADD522 may exert its antitumor activity by increasing mitochondrial driven cellular ROS levels. Collectively, our data suggest in vitro proof-of-concept that supports inhibition of mitochondrial ATP synthase and ROS generation as contributors to the effectiveness of CADD522 in suppression of tumor growth.Human breast cancer which affects 1/8 women is rare at a cellular level. Even in the setting of germline BRCA1/BRCA2, which is present in all breast cells, solitary cancers or cancers arising at only several foci occur. The overwhelming majority of breast cells (109-1012 cells) resist transformation. Our hypothesis to explain this rareness of transformation is that mammary oncogenesis is regulated by the cell of origin's critical window of differentiation so that target cells outside of this window cannot transform. Our novel hypothesis differs from both the multi-hit theory of carcinogenesis and the stem/progenitor cell compartmental theory of tumorigenesis and utilizes two well established murine transgenic models of breast oncogenesis, the FVB/N-Tg (MMTV-PyVT)634Mul/J and the FVB-Tg (MMTV-ErbB2) NK1Mul/J. Tail vein fibroblasts from each of these transgenics were used to generate iPSCs. When select clones were injected into cleared mammary fat pads, but not into non-orthotopic sites of background mice, they exhibited mammary ontogenesis and oncogenesis with the expression of their respective transgenes. iPSC clones, when differentiated along different non-mammary lineages in vitro, were also not able to exhibit either mammary ontogenesis or oncogenesis in vivo. Therefore, in vitro and in vivo regulation of differentiation is an important determinant of breast cancer oncogenesis.

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