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Purpose The presence of bone metastasis at baseline has been associated with dismal prognosis under immunotherapy in advanced non-small cell lung cancer (NSCLC). Response Evaluation Criteria in Solid Tumors (RECIST) criteria may be limited for bone-specific response evaluation. Whether their assessment through MD Anderson (MDA) criteria predict immunotherapy efficacy is unknown. Materials and methods We conducted a single-center retrospective study to assess the use of MDA criteria in evaluating bone metastasis in NSCLC treated with immunotherapy. Radiological imaging were reviewed to classify bone lesions as osteolytic, osteoblastic, or mixed. Bone response to treatment data was classified according to MDA criteria. Results 222 patients received single-agent immunotherapy. The presence of bone metastasis increased the risk of death both in the univariate (HR: 1.46, 95% CI, 1.05–2.03, p = 0.024) and in the multivariate model (HR: 1.61, 95% CI, 1.10–2.36, p = 0.015). According to MDA criteria, 57.3% of patients had progressive disease as best response, 29.5% stable disease, 11.4% partial response and 1.6% complete response. Bone-specific objective response was associated with a significantly increased median overall survival (11.3 vs. 3.1 months, p = 0.027) and longer median progression-free survival (6 vs. 2.1 months, p = 0.056). The median time to bone failure (TBF) was 2.4 months (IQR, 1.67–3.0). In 25.7% of cases, TBF was shorter than progression-free survival according to RECIST 1.1 criteria. TBF was positively correlated with overall survival (HR = 0.73, p = 0.00019). Conclusions MDA criteria represent a reliable tool in assessing bone-specific response, offering a more accurate evaluation with the aim to earlier predict survival outcomes or treatment failure compared to RECIST criteria for advanced NSCLC patients receiving immunotherapy.

Purpose of Review In this review, we analyzed the current landscape of non-PD-(L)1 targeting immunotherapy. Recent Findings The advent of immunotherapy has completely changed the standard approach toward advanced NSCLC. Inhibitors of the PD-1/PD-L1 axis have quickly taken place as first-line treatment for NSCLC patients without targetable “driver” mutations. However, a non-negligible portion of patients derive modest benefit from immune-checkpoint inhibitors, and valid second-line alternatives are lacking, pushing researchers to analyze other molecules and pathways as potentially viable targets in the struggle against NSCLC. Summary Starting from the better characterized CTLA-4 inhibitors, we then critically collected the actual knowledge on NSCLC vaccines as well as on other emerging molecules, many of them in their early phase of testing, to provide to the reader a comprehensive overview of the state of the art of immunotherapy in NSCLC beyond PD-1/PD-L1 inhibitors.

e21078 Background: In advanced EGFR-mutated non-small cell lung cancer (NSCLC) population, osimertinib represents the standard of care both for EGFR tyrosine kinase (TK) inhibitor-naive patients and for those with EGFR-mutated NSCLC harboring the T790M mutation and progressed following prior EGFR-TK inhibitor. No clear data supports the relationship between body mass index (BMI) and osimertinib's efficacy. Methods: We conducted a single-center, retrospective study including advanced EGFR-mutated NSCLC patients treated with Osimertinib as second or subsequent lines from February 2016 to December 2020. We examined survival outcomes according to BMI among a BMI-low group ( < 25 Kg/mq2) and BMI-high group (≥25 Kg/mq2). Results: A total of 37 consecutive patients received osimertinib as second- or subsequent line at our Institution. The mean age was 63.5 years (range 34-83 years), 24 (65%) patients were female, 16 (59%) were former or never smokers, and 25 (67%) had three or more metastatic sites at the start of therapy. The BMI-low group includes 25 (67%) patients and the BMI-high group 12 (33%), respectively. Globally, the median overall survival (mOS) was 29.9 mo. (95% CI, 18.2 – NR) and median progression-free survival (mPFS) was 17.5 mo. (95% CI, 15.7-33.3). The median follow-up was 32.5 mo. (IQR, 13.35-42.06). The mPFS was 21.0 mo. (95 CI, 16.8 – NR) within the BMI-low group and 16.8 mo. (95 CI, 4.4 – NR) within the BMI-high group, respectively (p = 0.03). Analogously, the mOS within the BMI-low group was 29.9 mo. (95 CI, 20.8 – NR) versus 18.2 mo. (95 CI, 11.7- NR) for the BMI-high group (p = 0.01). A BMI ≥25 Kg/mq2 constituted an independent risk factor for mortality [HR 3.99, (95 CI, 1.2 – 13.2), p 0.02] at multivariate analysis, including also age and number of metastatic sites. The BMI-high group showed a non-significant tendency to progression [HR 2.76, (95 CI, 0.9 - 8.3), p 0.06] at the same multivariate analysis. Conclusions: In our experience, a BMI ≥25 Kg/mq2 negatively influenced survival outcomes of 2nd-line osimertinib' treated NSCLC patients. More comprehensive studies are warranted to confirm these findings.

Atomic-scale relationships between the structure of TiO2 surfaces and the physicochemical properties of surface sites, functional for titania-based applications, can be obtained from IR spectroscopy by using carbon monoxide (CO) as a molecular probe. In the literature, it is reported that strongly unsaturated cationic Ti sites (Lewis acid), which are important for reactivity, should cause a large upshift of the CO stretching frequency. By using IR spectroscopy of CO on TiO2 nanomaterials and theoretical analyses, here this model is challenged. It is shown that the stretching frequency of adsorbed CO results from a facet-dependent and synergic CO-surface donation (upshift) - surface-CO backdonation (downshift) mechanism. These results imply that the interaction of adsorbed molecules with the Ti centers is tuned by the surface oxygen atoms of the first coordination sphere, which play an active role as indirect electron density donors (Lewis base).

The reactivities of various commercial and lab-made oxide samples (e.g., γ-Al2O3, CeO2, ZrO2 and TiO2) in the heterogeneous catalytic synthesis of N-phenylpropionamide (T, 383 K) from aniline and propanoic acid have been investigated. All the materials studied drive the direct synthesis of the amide to an extent depending on both the chemical and structural properties. A 0th-order kinetic dependence on the substrate concentrations suggests that the reaction proceeds via a Langmuir–Hinshelwood (L–H) pathway under kinetic control of the adsorption–desorption steps (the rate determining step, r.d.s.). The comparative analysis of the activity data on the basis of the relative surface specific kinetic constant discloses a superior surface reactivity of TiO2, CeO2 and ZrO2 over the γ-Al2O3 system, and also highlights marked differences in the catalytic functionality of the titania samples. IR spectroscopic studies of the carboxylic acids and amine adsorption and interaction patterns show the formation of the bidentate, bridging, and unidentate carboxylate intermediates accounting for the different amidation functionalities of the studied materials.

In situ IR and mass spectrometry evidence for the catalytic formation on SiO2 and TiO2 surfaces of glycine oligomers (poly-Gly) up to 16 units long by successive feeding with monomers from the vapor phase is presented. Parallel experiments carried out on hydroxyapatite resulted in the unreactive adsorption of Gly, thus indicating that the oligomerization was specifically catalyzed by the surfaces of SiO2 and TiO2 . Furthermore, the poly-Gly moved on the surface when contacted with H2 O vapor and formed self-assembled aggregates containing both helical and β-sheet-like structural motifs. These results indicate that polypeptides formed by the condensation of amino acids adsorbed on a mineral surface can evolve into structured supramolecular assemblies.

The development of green protocols for amide bond formation is a major socioeconomic goal for chemical and pharmaceutical industries and an important challenge for academic research. We herein report a protocol for the quantitative conversion of carboxylic acids and amines to form amides at 100 °C in the presence of a TiO2 powder catalyst, under monomodal microwave irradiation. The sustainability of the process appears to be augmented by the ease with which the catalyst is recycled.

Loss of MeCP2 (Methyl CpG binding protein 2) in Rett syndrome (RTT) causes brain weight decrease, shrinkage of the cortex with reduced dendritic arborization, behavioral abnormalities, seizures and cardio-respiratory complications. The observed monoamine neurotransmitters reduction in RTT suggested antidepressants as a possible therapy. We treated MeCP2-null mice from postnatal-day 28 for two weeks with desipramine, already tested in RTT, or mirtazapine, an antidepressant with limited side-effects, known to promote GABA release. Mirtazapine was more effective than desipramine in restoring somatosensory cortex thickness by fully rescuing pyramidal neurons dendritic arborization and spine density. Functionally, mirtazapine treatment normalized heart rate, breath rate, anxiety levels and eliminated the hopping behavior observed in MeCP2-null mice, leading to improved phenotypic score. These morphological and functional effects of mirtazapine were accompanied by reestablishment of the GABAergic and glutamatergic receptor activity recorded in cortex and brainstem tissues. Thus, mirtazapine can represent a new potential pharmacological treatment for the Rett syndrome.

The species resulting from insertion of 12CO2 and 13CO2 into titanium(IV) butoxide is for the first time fully characterized by means of infrared and nuclear magnetic resonance spectroscopy. Results show formation of Ti-monobutylcarbonate, that easily undergoes nucleophilic attack by an aliphatic amine. The hydrolysis of the resulting species produces butylcarbamate and dibutylcarbonate as the only main products. Characterization results of the carbonate-like adduct, along with its reactivity with amine molecules open the route to new ways of CO2 utilization as building block for valuable organic compounds.

Surface hydroxy groups are known to play a significant role in the photocatalytic behavior of TiO2. The molecular or dissociative character of H2O adsorption on titania is strongly affected by the local surface structure, but dissociation, producing −OH, should prevail on surface sites with a high degree of coordinative unsaturation. Here we report an IR investigation of hydroxy groups on low coordination sites of TiO2 P25 (Degussa), a commercial titania powder considered a staple in the field of heterogeneous photocatalysis. The presence of coordinatively defective surface terminations well agrees with the roughness of the border of TiO2 particles observed by high resolution transmission electron microscopy. Furthermore, IR spectra of adsorbed CO were used to probe the Lewis acidity of surface Ti4+ ions exposed after the removal of water molecules and hydroxy groups. Evidence for two additional types of surface cationic sites with respect those reported in the literature was found.

Epigenetic modifications such as histone acetylation in cortical or allocortical regions have been shown to be necessary for the formation of long-term memories. Here we investigated whether similar changes were occurring also in the ventral striatum and whether they are necessary for the consolidation of aversive memory. To this purpose we performed immediate post-training focal administrations of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, 5, 10 or 15. ?g/side) or the DNA methyltransferase (DNMT) inhibitor, 5-aza-2'-deoxycytidine (5-AZA, 0.0625 or 0.125. ?g/side) in the ventral striatum of mice trained in one-trial inhibitory avoidance task. Intra-ventral striatal SAHA administrations, immediately after training, improved memory retention. Opposite effects were found with 5-AZA. We also found that training in the one-trial inhibitory avoidance is accompanied by increased acetylation of specific residues that can be further increased by intra-VS SAHA administrations. Intra-VS 5-AZA administrations on the other hand reduced training-induced histones acetylation at the same residues. These findings imply the occurrence of histone acetylation in the ventral striatum in order to store aversive memory. Moreover, they suggest that the effects induced by the DNMT inhibitor 5-AZA may at least partially due to blockade of H3 and H4 acetylation. These results suggest that the contemporary activation of similar molecular mechanisms might be needed in different brain regions to enable the formation of long-term memories. © 2014 Elsevier B.V.

Integrated studies of CO on truncated bipyramidal TiO(2) anatase nanoparticles mainly exposing smooth (101) surfaces provide the missing link between TiO(2) single crystals and commercial TiO(2) nanopowders with complex morphology. The synergy among high resolution transmission electron microscopy, IR spectroscopy and modeling correlates adsorbed CO stretching frequency to anatase surface types, and reveals how disorder of the adsorbed CO layer affects CO/TiO(2) IR bands. Comparison of the two TiO(2) nanoparticle types highlights the role of low coordination Ti(4+) sites selectively present on TiO(2) P25 in the photocatalytic decomposition of H(2)O(2), an important Reactive Oxygen Species (ROS) formed in photocatalytic processes.

In this chapter, the possibilities to highlight atomic/molecular details of the surface of nanomaterials by IR spectroscopy of their interaction with molecules in controlled conditions are reviewed. For this objective, information on the experimental setups and procedures is also provided; particular attention has been devoted to the use of different probe molecules (CO, CH3CN, and H2O). Such molecules, when adsorbed in controlled conditions, become useful “molecular tools because of the sensitivity of their vibrational features to the physical/chemical properties of surface sites.

Doping for the environment: Electron paramagnetic resonance and X-ray photoelectron spectroscopy investigations prove-for the first time-that the proximity of surface F and surface/second layer B generates hole-trapping species responsible for a remarkable photocatalytic activity of rutile TiO 2, even for low-surface-area materials. A careful synthetic design of doped TiO 2 containing a high concentration of these species may lead to significantly enhanced performances in pollutant degradation.