Additive Manufacturing of Ceramics Enabled by Flash Pyrolysis of Polymer Precursors with Nanoscale Layers

We show that a polymer‐based route to ceramics can be implemented into additive manufacturing by reducing the time for pyrolysis to about a second, which we call flash pyrolysis. Repetitive deposition of nanometer scale coatings of the ceramic, in this way, is employed to create defect‐free infiltrations of carbon fiber composites. The mechanical strength of the fibers is retained in the composite. Excellent wetting properties of the polymer precursor permits three‐dimensional, conformal coating through the three stages of infiltration: nanoscale coating of the single fibers, filling of interstitial spaces between the fibers, and a buildup of the coating over the entire composite. The flash pyrolysis method will enable a new genre of polymer‐derived ceramics made into net shape by this unusual method of additive manufacturing.     

Identification and Structure–Activity Relationship Studies of Small‐Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1

The methyllysine reader protein Spindlin1 has been implicated in the tumorigenesis of several types of cancer and may be an attractive novel therapeutic target. Small‐molecule inhibitors of Spindlin1 should be valuable as chemical probes as well as potential new therapeutics. We applied an iterative virtual screening campaign, encompassing structure‐ and ligand‐based approaches, to identify potential Spindlin1 inhibitors from databases of commercially available compounds. Our in silico studies coupled with in vitro testing were successful in identifying novel Spindlin1 inhibitors. Several 4‐aminoquinazoline and quinazolinethione derivatives were among the active hit compounds, which indicated that these scaffolds represent promising lead structures for the development of Spindlin1 inhibitors. Subsequent lead optimization studies were hence carried out, and numerous derivatives of both lead scaffolds were synthesized. This resulted in the discovery of novel inhibitors of Spindlin1 and helped explore the structure–activity relationships of these inhibitor series.     

Novel Therapeutic Opportunities in Neoadjuvant Setting in Urothelial Cancers: A New Horizon Opened by Molecular Classification and Immune Checkpoint Inhibitors

Muscle invasive bladder cancer (MIBC) is a widespread malignancy with a worse prognosis often related to a late diagnosis. For early-stage MIBC pts, a multidisciplinary approach is mandatory to evaluate the timing of neoadjuvant chemotherapy (NAC) and surgery. The current standard therapy is platinum-based NAC (MVAC-methotrexate, vinblastine, doxorubicin, and cisplatin or Platinum–Gemcitabine regimens) followed by radical cystectomy (RC) with lymphadenectomy. However, preliminary data from Vesper trial highlighted that dose-dense NAC MVAC is endowed with a good pathological response but shows low tolerability. In the last few years, translational-based research approaches have identified several candidate biomarkers of NAC esponsiveness, such as ERCC2, ERBB2, or DNA damage response (DDR) gene alterations. Moreover, the recent consensus MIBC molecular classification identified six molecular subtypes, characterized by different sensitivity to chemo- or targeted or immunotherapy, that could open a novel procedure for patient selection and also for neoadjuvant therapies. The Italian PURE-01 phase II Trial extended data on efficacy and resistance to Immune Checkpoint Inhibitors (ICIs) in this setting. In this review, we summarize the most relevant literature data supporting NAC use in MIBC, focusing on novel therapeutic strategies such as immunotherapy, considering the better patient stratification and selection emerging from novel molecular classification.     

Platinum(II) Complexes Bearing Triphenylphosphine and Chelating Oximes: Antiproliferative Effect and Biological Profile in Resistant Cells

Platinum(II) complexes of the type [Pt(Cl)(PPh₃){(κ²-N,O)-(1{C(R)=N(OH)-2(O)C₆H₄})}] with R=Me, H, ( 1 and 2 ) were synthesized and characterized. Single-crystal X-ray diffraction confirmed the proposed (SP4-3) configuration for 1 . Study of the antiproliferative activity, performed on a panel of human tumor cell lines and on mesothelial cells, highlighted complex 2 as the more effective. In particular, it showed a remarkable cytotoxicity in ovarian carcinoma cells (A2780) and interestingly, a significant antiproliferative effect on cisplatin resistant cells (A2780cis). Investigation into the intracellular mechanism of action demonstrated that 2 had a lower ability to platinate DNA than did cisplatin, which was taken as reference, and a notably higher uptake in resistant cells. A significant accumulation in mitochondria, along with the ability to induce concentration-dependent mitochondrial membrane depolarization and intracellular reactive oxygen species production, allowed us to propose a mitochondrion-mediated pathway as responsible for the interesting cytotoxic profile of complex 2 .     

The Role of Testosterone in the Elderly: What Do We Know?

Testosterone is the most important hormone in male health. Aging is characterized by testosterone deficiency due to decreasing testosterone levels associated with low testicular production, genetic factors, adiposity, and illness. Low testosterone levels in men are associated with sexual dysfunction (low sexual desire, erectile dysfunction), reduced skeletal muscle mass and strength, decreased bone mineral density, increased cardiovascular risk and alterations of the glycometabolic profile. Testosterone replacement therapy (TRT) shows several therapeutic effects while maintaining a good safety profile in hypogonadal men. TRT restores normal levels of serum testosterone in men, increasing libido and energy level and producing beneficial effects on bone density, strength and muscle as well as yielding cardioprotective effects. Nevertheless, TRT could be contraindicated in men with untreated prostate cancer, although poor findings are reported in the literature. In addition, different potential side effects, such as polycythemia, cardiac events and obstructive sleep apnea, should be monitored. The aim of our review is to provide an updated background regarding the pros and cons of TRT, evaluating its role and its clinical applicability in different domains.     

Systematic Review on Tumor Microenvironment in Glial Neoplasm: From Understanding Pathogenesis to Future Therapeutic Perspectives

Despite the multidisciplinary management in the treatment of glioblastomas, the average survival of GBM patients is still 15 months. In recent years, molecular biomarkers have gained more and more importance both in the diagnosis and therapy of glial tumors. At the same time, it has become clear that non neoplastic cells, which constitute about 30% of glioma mass, dramatically influence tumor growth, spread, and recurrence. This is the main reason why, in recent years, scientific research has been focused on understanding the function and the composition of tumor microenvironment and its role in gliomagenesis and recurrence. The aim of this review is to summarize the most recent discovery about resident microglia, tumor-associated macrophages, lymphocytes, and the role of extracellular vesicles and their bijective interaction with glioma cells. Moreover, we reported the most recent updates about new therapeutic strategies targeting immune system receptors and soluble factors. Understanding how glioma cells interact with non-neoplastic cells in tumor microenvironment is an essential step to comprehend mechanisms at the base of disease progression and to find new therapeutic strategies for GBM patients. However, no significant results have yet been obtained in studies targeting single molecules/pathways; considering the complex microenvironment, it is likely that only by using multiple therapeutic agents acting on multiple molecular targets can significant results be achieved.     

Sugar and dietary fibre composition influence, by different hormonal response, the satiating capacity of a fruit-based and a β-glucan-enriched beverage

In this study the satiating capacity of three beverages containing 3 g barley β-glucan, or 2.5 g dietary fibre (DF) from fruit, or without DF (control) was evaluated. Fourteen healthy volunteers were randomized to have isocaloric breakfasts including one of the beverages in different occasions. Appetite ratings over 3 h post-breakfast and energy intakes at ad libitum lunch, blood glucose, insulin, ghrelin, PYY, GLP-1, GIP, and PP concentrations, and 24 h food intake, were assessed. The bevaerages containing DF increased fullness and satiety over 3 h post-breakfast, but only the β-glucan-enriched vs. the control significantly reduced energy intakes by 18% at lunch and 40% over the rest of the day. Blood ghrelin and PP responses were differently modulated by beverages. The fruit-based and the β-glucan-enriched beverage suppressed by 8.9% and 8.1% ghrelin response over the 3 h and the first hour post-breakfast, respectively, while only the latter increased PP response by 34.6%, compared to the control. A sucrose-sweetened beverage providing 3 g barley β-glucans can control food intake by modulating PP response and it can even reduce 24 h energy intake. Ghrelin suppression by fruit dietary fibre and mixed sugars was not sufficient to significantly reduce food intake compared to the control.     

Reactivity of V2O5&z.sbnd;WO3TiO2 de-NOx catalysts by transient methods

The reactivity of ternary V₂O₅&z.sbnd;WO₃TiO₂ de-NO_xing catalysts with compositions similar to those of commercial catalysts (WO₃ ca. 9% w/w, V₂O₅ < 2% w/w) is investigated by transient techniques (temperature programmed desorption, TPD; temperature programmed surface reaction, TPSR; and temperature programmed reaction, TPR). The results indicate that the reactivity of the ternary catalysts in the SCR reaction increases on increasing the vanadia loading, and that the ternary catalysts are more active than the corresponding binary vanadia-titania samples with the same V₂O₅ loading. Indeed the SCR reaction is monitored at lower temperatures and high NO conversions are also preserved at high temperatures. TPSR and TPR data show that at low temperatures the SCR reaction occurs via a redox mechanism that involves at first the participation of the catalyst lattice oxygen and then the reoxidation of the reduced sites by gas-phase oxygen. Based on TPSR and TPR data, the higher reactivity of the ternary catalysts has been related to their superior redox properties, in line with previous chemico-physical characterisation studies. The catalyst redox properties thus appear as a key-factor in controlling the reactivity of V₂O₅&z.sbnd;WO₃TiO₂ de-NO_xing catalysts at low temperatures. The results also show that at high temperatures the surface acidity plays an important role in the adsorption and activation of ammonia.