Immuno-Metabolism and Microenvironment in Cancer: Key Players for Immunotherapy

Immune checkpoint inhibitors (ICIs) have changed therapeutic algorithms in several malignancies, although intrinsic and secondary resistance is still an issue. In this context, the dysregulation of immuno-metabolism plays a leading role both in the tumor microenvironment (TME) and at the host level. In this review, we summarize the most important immune-metabolic factors and how they could be exploited therapeutically. At the cellular level, an increased concentration of extracellular adenosine as well as the depletion of tryptophan and uncontrolled activation of the PI3K/AKT pathway induces an immune-tolerant TME, reducing the response to ICIs. Moreover, aberrant angiogenesis induces a hypoxic environment by recruiting VEGF, Treg cells and immune-suppressive tumor associated macrophages (TAMs). On the other hand, factors such as gender and body mass index seem to affect the response to ICIs, while the microbiome composition (and its alterations) modulates both the response and the development of immune-related adverse events. Exploiting these complex mechanisms is the next goal in immunotherapy. The most successful strategy to date has been the combination of antiangiogenic drugs and ICIs, which prolonged the survival of patients with non-small-cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), while results from tryptophan pathway inhibition studies are inconclusive. New exciting strategies include targeting the adenosine pathway, TAMs and the microbiota with fecal microbiome transplantation

Minimization of defects generation in laser welding process of steel alloy for automotive application

Laser welding (LW) thanks to its flexibility, limited energy consumption and simple realization has a prominent role in several industrial sectors. LW process requires careful parameters' tuning to avoid generating internal defects in the microstructure or a poor weld depth, which reduce the joining mechanical strength and result in waste. This work exploits a supervised machine learning algorithm to optimize the process parameters to minimize the generated defects, while catering for design specifications and tolerances to predict defect generation probability. The work outputs a predictive quality control model to reduce non-destructive controls in the LW of aluminum for automotive applications

Overcritical Rotation of a Trapped Bose-Einstein Condensate

The rotational motion of an interacting Bose-Einstein condensate confined by a harmonic trap is investigated by solving the hydrodynamic equations of superfluids, with the irrotationality constraint for the velocity field. We point out the occurrence of an overcritical branch where the system can rotate with angular velocity larger than the oscillator frequencies. We show that in the case of isotropic trapping the system exhibits a bifurcation from an axisymmetric to a triaxial configuration, as a consequence of the interatomic forces. The dynamical stability of the rotational motion with respect to the dipole and quadrupole oscillations is explicitly discussed.Comment: 6 pages, 3 postscript figure

Search-Based Motion Planning for Performance Autonomous Driving

Driving on the limits of vehicle dynamics requires predictive planning of future vehicle states. In this work, a search-based motion planning is used to generate suitable reference trajectories of dynamic vehicle states with the goal to achieve the minimum lap time on slippery roads. The search-based approach enables to explicitly consider a nonlinear vehicle dynamics model as well as constraints on states and inputs so that even challenging scenarios can be achieved in a safe and optimal way. The algorithm performance is evaluated in simulated driving on a track with segments of different curvatures.Comment: Accepted to IAVSD 201

Evaluation of the bactericidal activity of a hyaluronic acid-vehicled clarithromycin antibiotic mixture by confocal laser scanning microscopy

Confocal laser scanning microscopy (CLSM) was used to evaluate the antibacterial effect and depth of action of a novel clarithromycin-containing triple antibiotic mixture, which was proposed for root canal disinfection in dental pulp regeneration. A previous study reported that this mixture had no tooth discoloration effects in vitro. After infection with Enterococcus faecalis for 3 weeks, the dentinal tubules in the cylindrical root specimens were exposed to different antibiotic mixtures: ciprofloxacin, metronidazole and minocycline (3-MIX); ciprofloxacin, metronidazole and clarithromycin (3-MIXC) and ciprofloxacin and metronidazole (2-MIX). Each antibiotic formulation was mixed with macrogol (MG) or hyaluronic acid (HA) vehicles. CLSM and viability staining were used to quantitatively analyze the mean depth of the antibacterial effect and the proportions of dead and live bacteria inside the dentinal tubules. The 3-MIX and 3-MIXC demonstrated a similar depth of action. The mean proportion of dead bacteria was similar in the 3-MIX and 3-MIXC groups, and both were statistically higher than that of 2-MIX (p = 0.014). Each antibiotic mixture showed a higher bactericidal efficacy if conveyed with HA, compared to MG (3-MIX, p = 0.019; 3-MIXC, p = 0.013 and 2-MIX, p = 0.0125). The depth of action and the antibacterial efficacy of 3-MIXC seemed comparable with 3-MIX

Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis

BACKGROUND: Seasonal variation has been reported in diagnosis of eosinophilic oesophagitis (EoE), but results are not consistent across studies and there are no national-level data in the USA. AIM: To determine if there is seasonal variation in diagnosis of oesophageal eosinophilia and EoE in the USA, while accounting for factors such as climate zone and geographic variation. METHODS: This was a cross-sectional study using a USA national pathology database. Patients with oesophageal eosinophilia (≥15 eosinophils per high-power field) comprised the primary case definition and were compared to those with normal oesophageal biopsies. We calculated the crude and adjusted odds of oesophageal eosinophilia by season, as well as by day of the year. Sensitivity analyses were performed using more restrictive case definitions of EoE, and after stratification by climate zone. RESULTS: Exactly, 14 524 cases with oesophageal eosinophilia and 90 459 normal controls were analysed. The adjusted odds of oesophageal eosinophilia were higher in the late spring and summer months, with the highest odds in July (aOR: 1.13; 95% CI: 1.03-1.24). These findings persisted with increasing levels of oesophageal eosinophilia, as well as across EoE case definitions. Seasonal variation was strongest in temperate and cold climates, and peak diagnosis varied by climate zone. CONCLUSIONS: There is a mild but consistent seasonal variation in the diagnosis of oesophageal eosinophilia and EoE, with cases more frequently diagnosed during summer months. These findings take into account climate and geographic differences, suggesting that aeroallergens may contribute to disease development or flare

Preclinical immunotherapy with Cytokine-Induced Killer lymphocytes against epithelial ovarian cancer

Despite improvements in surgery and medical treatments, epithelial ovarian cancer (EOC) remains the most lethal gynaecological malignancy. Aim of this study is to investigate the preclinical immunotherapy activity of cytokine-induced killer lymphocytes (CIK) against epithelial ovarian cancers, focusing on platinum-resistant settings. We generated CIK ex vivo starting from human peripheral blood samples (PBMCs) collected from EOC patients. Their antitumor activity was tested in vitro and in vivo against platinum-resistant patient-derived ovarian cancer cells (pdOVCs) and a Patient Derived Xenograft (PDX), respectively. CIK were efficiently generated (48 fold median ex vivo expansion) from EOC patients; pdOVCs lines (n = 9) were successfully generated from metastatic ascites; the expression of CIK target molecules by pdOVC confirmed pre and post treatment in vitro with carboplatin. The results indicate that patient-derived CIK effectively killed autologous pdOVCs in vitro. Such intense activity was maintained against a subset of pdOVC that survived in vitro treatment with carboplatin. Moreover, CIK antitumor activity and tumor homing was confirmed in vivo within an EOC PDX model. Our preliminary data suggest that CIK are active in platinum resistant ovarian cancer models and should be therefore further investigated as a new therapeutic option in this extremely challenging setting