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In this paper, the recently proposed structural optimization strategy, the Galilei-Optimization (GO), is adapted for improving the toughness response of a holed two-dimensional lattice system made of a network of micro-beams whose geometrical arrangement was prescribed. By taking advantage of the possibility of minimizing stress gradients and stress peaks around the hole via GO, we redesigned the cross sections of the lattice beam elements, equalizing the stresses over the entire domain. Consequently, the resulting optimized microstructure highlighted a significant enhancement of the overall toughness due to a drastic decrease of the stress concentration factor in the hole proximity, preserving the initial stiffness and lowering the total overall weight. To validate the robustness of the procedure and the numerical Finite Element outcomes, two non-optimized and optimized structures were actually built up through 3D printing and tested in the laboratory under the same boundary conditions used for the simulations. This evidence confirmed the effectiveness of the proposed method in obtaining optimized beam-like plates with high toughness, which could pave the way for designing new light materials with extreme mechanical performance well beyond the sole stiffness and strength.

Nowadays, engine experimental research represents a very expensive field within the automotive industry, but it remains fundamental for engine and vehicle development. The present work aims to investigate a novel approach for engine control system calibration, by adopting machine learning techniques to model physical parameters of the engine starting from experimental data measured at the test bench. The main goal is to create a methodology which accelerates the calibration process without losing accuracy. A model that estimates air mass flow is created by adopting either a tree ensemble model or an artificial neural network trained on a small dataset, which was previously acquired at the test bench using a random calibration of the volumetric efficiency map. The model’s performance is first validated on a larger, random dataset. Then, the volumetric efficiency calculated from the air mass flow model estimation is used to calibrate the transfer function of the Engine Control Unit. Finally, the sensitivity of the model error correlated with the number of data points acquired is used in order to determine the best practice for a Design Of Experiment, which minimizes data acquisition. The methodology proposed can lead to reduced time and costs of the whole calibration process of the engine, without losing accuracy. The analysis was conducted on the entire vehicle, which is crucial for drivability, especially in motorcycles since they are highly sensitive to air-to-fuel ratio adjustments. This work demonstrates that machine learning models can be adopted for the fine-tuning of the calibration process, which is normally performed manually.

The identification of new effective therapeutic options for non-small-cell lung cancer (NSCLC) represents a crucial challenge in oncology. Recent studies indicate that cancer-associated fibroblasts (CAFs) participate in tumor progression by establishing a favorable microenvironment that promotes cancer progression. Therefore, the development of strategies inhibiting the interplay between CAFs and cancer cells is considered a winning approach for the development of effective anti-cancer drugs. Among other factors, the signal transducer and activator of transcription-3 (STAT3) has been reported as a key mediator of CAF oncogenic actions, representing a promising therapeutic target. Here, we applied an aptamer-based conjugate (named Gint4.T-STAT3), containing a STAT3 siRNA linked to an aptamer binding and inhibiting the platelet-derived growth factor receptor (PDGFR)β, to obtain STAT3-specific silencing and interfere with CAF pro-tumorigenic functions. We demonstrated that this molecule effectively delivers the STAT3 siRNA in NSCLC cells, and blocks CAF-induced cancer cell growth and migration and reduced spheroid dimension. In addition, we found that Gint4.T-STAT3 alters CAF phenotype, thus functioning as a double-acting molecule able to inhibit the entire tumor bulk. Our data provide a proof of principle for the targeting of CAF pro-tumor functions through an aptamer-based drug, and can open innovative horizons in NSCLC therapy.

ABSTRACTThis study presents an original mapping of hydrological karst features of the Matese massif (southern Italy), whose relevance is given by large basal springs supplying millions of people and the hydroelectric exploitation of the major endorheic areas. We mapped dolines and endorheic areas from 1- and 5-meter Digital Elevation Models (DEM) using Geographic Information System (GIS) tools and techniques. Instead, ponors, caves, and karst springs were mapped mainly based on cartographic and literature analyses. We identified 321 endorheic areas occupying 31% of the massif area and 489 dolines, distinguished in (i) solution (N = 433) and collapse dolines (N = 56), the latter located in the discharge zones of the massif and connected to ascendant flows of CO2- and H2S-rich groundwater. The map shows the hydrological features of a karst massif from a more detailed and new perspective, and it can be helpful in water management, groundwater resource protection, environmental safeguarding, and ecological development.

Abstract The rechallenge strategy is based on the concept that a subset of patients with RAS wild‐type (WT) metastatic colorectal cancer (mCRC) could still benefit of epidermal growth factor receptor (EGFR) inhibition, after progression to an anti‐EGFR based‐therapy. We performed a pooled analysis of two‐phase II prospective trials to determine the role of rechallenge in third‐line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from CAVE and CRICKET trials that received as third‐line therapy cetuximab rechallenge were collected. Overall survival (OS), Progression‐free survival (PFS), Overall response rate (ORR), Stable disease (SD) >6 months were calculated. Adverse events were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95% Confidence Interval, CI 3.0–4.9) with median OS (mOS) of 16.9 months (95% CI 11.7–22.1). For CRICKET patients, mPFS was 3.9 months (95% CI 1.7–6.2); mOS was 13.1 months (95% CI 7.3–18.9) with OS rates at 12, 18, and 24 months of 62%, 23%, and 0%, respectively. For CAVE patients, mPFS was 4.1 months (95% CI 3.0–5.2); mOS was 18.6 months (95% CI 11.7–25.4) with OS rates at 12, 18, 24 months of 61%, 52%, 21%, respectively. Skin rash was more frequently reported in CAVE trial (87.9% vs. 30.8%; p = 0.001), whereas a increased incidence of hematological toxicities was observed in CRICKET trial (53.8%% vs. 12.1%; p = 0.003). Third‐line cetuximab rechallenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy.

Here the authors generate an RNA-based platform to neutralize the major epigenetic player DNMT1. Using this targeted approach, aberrant DNA methylation in cancer can be corrected.

The LHC heavy-ion program with ^{208}Pb^{82+} beams will benefit from a significant increase of the beam intensity when entering its high-luminosity era in Run 3 (2023). The stored energy is expected to surpass 20 MJ per beam. The LHC is equipped with a betatron collimation system, which intercepts the transverse beam halo and protects sensitive equipment such as superconducting magnets against beam losses. However, nuclear fragmentation and electromagnetic dissociation of ^{208}Pb^{82+} ions in collimators generates a flux of secondary fragments, which are lost in downstream dispersion suppressor and arc cells. These secondary ions may pose a performance limitation in upcoming runs since they can induce magnet quenches. In order to mitigate this risk, an alternative collimation technique, relying on bent crystals as primary collimators, will be used in forthcoming heavy-ion runs. In this paper, we study the power deposition in superconducting magnets by means of tracking and fluka shower simulations, comparing the standard collimation system against the crystal-based one. In order to quantify the predictive ability of the simulation model, we present absolute benchmarks against beam loss monitor measurements from the 2018 ^{208}Pb^{82+} run at 6.37 ZTeV. The benchmarks cover several hundred meters of beamline, from the primary collimators to the first arc cells. Based on these studies, we provide a detailed analysis of ion fragmentation and leakage to the cold magnets and quantify the expected quench margin in future ^{208}Pb^{82+} runs.

The aim of the present study was to investigate the culturable microflora of pool frogs (Pelophylax lessonae) and their belonging aquatic environment. A total of 60 samples (56 frog cutaneous swabs, 4 water samples) were inoculated onto different selective and differential agar plates to isolate Gram-positive and Gram-negative bacteria or yeasts. Microbial investigation of the water hosting frogs was also performed. Isolates were identified by API system and their antibiotic resistance profiles were evaluated by disk diffusion method on Mueller Hinton agar plates. Aeromonas hydrophila and En-terococcus durans were detected in almost all collected samples. Many of the bacterial isolates showed multidrug-resistant profiles. Importantly, this study highlights that skin frog microbiota is correlated to the belonging environment, and, moreover, some isolated bacterial strains resulted to be of interest in animal and public health, since the park was frequented by visitors of all ages.

1,3:2,4-Dibenzylidene-D-sorbitol (DBS) and 12-hydroxystearic acid (12-HSA) are well-known as low-molecular-weight organogelators (LMOGs) capable of gelling an organic liquid phase. Considering their unique chemical and physical properties, we assessed their potential effects in new lipstick formulations by discrimination testing; in vitro measurements of the sun protection factor (SPF); and thermal, mechanical and texture analyzes. DBS and 12-HSA were used to formulate four types of lipsticks: L1 (1% DBS), L2 (10% 12-HSA), L3 (1.5% DBS) and L4 (control, no LMOGs). The lipsticks were tested for sensory perception with an untrained panel of 16 consumers. LMOG formulations exhibited higher UVA protection factor (UVA-PF) and in vitro SPF, particularly in the 12-HSA-based lipstick. Regarding thermal properties, the 12-HSA-based lipstick and those without LMOGs were more heat-amenable compared to thermoresistant DBS-based lipsticks. The results also showed the viscoelastic and thermally reversible properties of LMOGs and their effect of increasing pay-off values. In general, the texture analysis indicated that 12-HSA-based lipstick was significantly harder to bend compared to control, while the other formulations became softer and easier to bend throughout the stability study. This work suggests the potential use of LMOGs as a structuring agent for lipsticks, paving the way towards more photoprotective and sustainable alternatives.

Reconstruction after excision of infiltrating basal cell carcinomas (BCCs) of the upper pole of the ear can be achieved with different techniques. The concept of spare-part surgery, which allows the surgeon to perform primary reconstruction of a defect without harvesting tissue from the adjacent areas, has been applied to the ear anatomy. We describe our experience with the use of a fillet flap from the residual external ear in two patients out of a series of six, undergoing reconstruction of ear defects after infiltrating BCC resection between January 2011 and December 2014. Reconstruction with the fillet of pinna flap was proven to be an easy surgical technique with good functional and cosmetic outcomes. Our technique, not previously reported, enhances the versatility of ear reconstruction.