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Pancreatic cancer is a very aggressive disease with a dismal prognosis. The tumor microenvironment exerts immunosuppressive activities through the secretion of several cytokines, including interleukin (IL)-1. The IL-1/IL-1 receptor (IL-1R) axis is a key regulator in tumor-promoting T helper (Th)2- and Th17-type inflammation. Th2 cells are differentiated by dendritic cells endowed with Th2-polarizing capability by the thymic stromal lymphopoietin (TSLP) that is secreted by IL-1-activated cancer-associated fibroblasts (CAFs). Th17 cells are differentiated in the presence of IL-1 and other IL-1-regulated cytokines. In pancreatic cancer, the use of a recombinant IL-1R antagonist (IL1RA, anakinra, ANK) in in vitro and in vivo models has shown efficacy in targeting the IL-1/IL-1R pathway. In this study, we have developed sphingomyelin nanosystems (SNs) loaded with ANK (ANK-SNs) to compare their ability to inhibit Th2- and Th17-type inflammation with that of the free drug in vitro. We found that ANK-SNs inhibited TSLP and other pro-tumor cytokines released by CAFs at levels similar to ANK. Importantly, inhibition of IL-17 secretion by Th17 cells, but not of interferon-γ, was significantly higher, and at lower concentrations, with ANK-SNs compared to ANK. Collectively, the use of ANK-SNs might be beneficial in reducing the effective dose of the drug and its toxic effects. [ABSTRACT FROM AUTHOR]

Arylalkane-derived prodrugs of arylacetic acids are a small group of substances that have long been known for their anti-inflammatory action. Despite their ease of synthesis and good potential for the development of new potent and safe anti-inflammatory agents, this group of substances has not received much attention from researchers so far. Therefore, representative arylalkane derivatives were investigated through molecular docking techniques to verify the possible hepatic activation mode toward active metabolites by CYP1A2. In this regard, arylalkanoic acid prodrugs were docked with a crystallographic structure of human CYP1A2, in which the enzyme is co-crystallized with the selective competitive inhibitor α-naphthoflavone BHF. Of note, all the examined compounds proved capable of interacting with the enzyme active site in a manner similar to Nabumetone, thus confirming that a productive metabolic transformation is feasible. On the basis of these findings, it is possible to argue that subtle differences in the way CYP1A2 accommodates the ligands depend on the fine details of their molecular structures. Overall, these data suggest that compounds simply formed by an aromatic moiety bearing an appropriate alkane-derived chain could lead to innovative anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Letrozole is one of the most prescribed drugs for the treatment of breast cancer in post-menopausal women, and it is endowed with selective peripheral aromatase inhibitory activity. The efficacy of this drug is also a consequence of its long-lasting activity, likely due to its metabolic stability. The reactivity of cyano groups in the letrozole structure could, however, lead to chemical derivatives still endowed with residual biological activity. Herein, the chemical degradation process of the drug was studied by coupling multivariate curve resolution and spectrophotometric methodologies in order to assess a detailed kinetic profile. Three main derivatives were identified after drug exposure to different degradation conditions, consisting of acid-base and oxidative environments and stressing light. Molecular docking confirmed the capability of these compounds to accommodate into the active site of the enzyme, suggesting that the sustained inhibitory activity of letrozole may be at least in part attributed to the degradation compounds. [ABSTRACT FROM AUTHOR]

Virgin coconut oil (VCO) is a functional food with important health benefits. Its economic interest encourages fraudsters to deliberately adulterate VCO with cheap and low-quality vegetable oils for financial gain, causing health and safety problems for consumers. In this context, there is an urgent need for rapid, accurate, and precise analytical techniques to detect VCO adulteration. In this study, the use of Fourier transform infrared (FTIR) spectroscopy combined with multivariate curve resolution–alternating least squares (MCR-ALS) methodology was evaluated to verify the purity or adulteration of VCO with reference to low-cost commercial oils such as sunflower (SO), maize (MO) and peanut (PO) oils. A two-step analytical procedure was developed, where an initial control chart approach was designed to assess the purity of oil samples using the MCR-ALS score values calculated on a data set of pure and adulterated oils. The pre-treatment of the spectral data by derivatization with the Savitzky–Golay algorithm allowed to obtain the classification limits able to distinguish the pure samples with 100% of correct classifications in the external validation. In the next step, three calibration models were developed using MCR-ALS with correlation constraints for analysis of adulterated coconut oil samples in order to assess the blend composition. Different data pre-treatment strategies were tested to best extract the information contained in the sample fingerprints. The best results were achieved by derivative and standard normal variate procedures obtaining RMSEP and RE% values in the ranges of 1.79–2.66 and 6.48–8.35%, respectively. The models were optimized using a genetic algorithm (GA) to select the most important variables and the final models in the external validations gave satisfactory results in quantifying adulterants, with absolute errors and RMSEP of less than 4.6% and 1.470, respectively. [ABSTRACT FROM AUTHOR]

Background: Current evidence about intraoperative anastomotic testing after left-sided colorectal resections is still controversial. The aim of this study was to analyze the impact of Indocyanine Green fluorescent angiography (ICG-FA) and air-leak test (ALT) over standard assessment on anastomotic leakage (AL) rates according to surgeon's perception of anastomosis perfusion and/or integrity in clinical practice. Methods: A database of 2061 patients who underwent left-sided colorectal resections was selected from patients enrolled in a prospective multicenter study. It was retrospectively analyzed through a multi-treatment machine-learning model considering standard visual assessment (NW; No. = 899; 43.6%) as the reference treatment arm, compared to ICG-FA alone (WP; No. = 409; 19.8%), ALT alone (WI; No. = 420; 20.4%) or both (WPI; No. = 333; 16.2%). Twenty-four covariates potentially affecting the outcomes were included and balanced into the model within the subgroups. The primary endpoint was AL, the secondary endpoints were overall morbidity (OM), major morbidity (MM), reoperation for AL, and mortality. All the results were reported as odds ratio (OR) with 95% confidence intervals (95%CI). Results: The WPI subgroup showed significantly higher AL risk (OR 1.91; 95% CI 1.02–3.59; p 0.043), MM risk (OR 2.35; 95% CI 1.39–3.97; p 0.001), and reoperation for AL risk (OR 2.44; 95% CI 1.12–5.31; p 0.025). No other significant differences were recorded. Conclusions: This study showed that the surgeons' perception of both anastomotic perfusion and integrity (WPI subgroup) was associated to a significantly higher risk of AL and related morbidity, notwithstanding the extensive use of both ICG-FA and ALT testing. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) stands out as the most tremendous brain tumor, constituting 60% of primary brain cancers, accompanied by dismal survival rates. Despite advancements in research, therapeutic options remain limited to chemotherapy and surgery. GBM molecular heterogeneity, the intricate interaction with the tumor microenvironment (TME), and non-selective treatments contribute to the neoplastic relapse. Diagnostic challenges arise from GBM advanced-stage detection, necessitating the exploration of novel biomarkers for early diagnosis. Using data from the literature and a bioinformatic tool, the current manuscript delineates the molecular interplay between human GBM, astrocytes, and myeloid cells, underscoring selected protein pathways belonging to astroglia and myeloid lineage, which can be considered for targeted therapies. Moreover, the pivotal role of extracellular vesicles (EVs) in orchestrating a favorable microenvironment for cancer progression is highlighted, suggesting their utility in identifying biomarkers for GBM early diagnosis. [ABSTRACT FROM AUTHOR]

Nucleoside analogues (NAs) are a family of compounds which include a variety of purine and pyrimidine derivatives, widely used as anticancer and antiviral agents. For their ability to compete with physiological nucleosides, NAs act as antimetabolites exerting their activity by interfering with the synthesis of nucleic acids. Much progress in the comprehension of their molecular mechanisms has been made, including providing new strategies for potentiating anticancer/antiviral activity. Among these strategies, new platinum-NAs showing a good potential to improve the therapeutic indices of NAs have been synthesized and studied. This short review aims to describe the properties and future perspectives of platinum-NAs, proposing these complexes as a new class of antimetabolites. [ABSTRACT FROM AUTHOR]

On behalf of the BraYn Association Ets, we are pleased to present the Abstracts of the Fifth Brainstorming Research Assembly for Young Neuroscientists, which was held in Rome, Italy from 28–30 September 2022. We congratulate all the presenters on their research work and contribution. [ABSTRACT FROM AUTHOR]

Spontaneous Coronary Artery Dissection (SCAD) refers to the spontaneous separation of the layers of the vessel wall caused by intramural hemorrhage, with or without an intimal tear. The "typical" SCAD patient is a middle-aged woman with few traditional cardiovascular risk factors, and it's frequently associated with pregnancy. Because of its low incidence, its pathophysiology is not fully understood. SCAD presents as an acute coronary syndrome, with chest pain, dyspnea, syncope, or heartbeat, even if diagnosis and clinical handling are different: coronary angiography is currently the main tool to diagnose SCAD; however, in doubtful cases, the use of both invasive and noninvasive cardiovascular imaging methods such as intravascular ultrasound or optical coherence tomography may be necessary. This paper aims to review the current state of knowledge on SCAD to address its demographic features, clinical characteristics, management, and outcomes, focusing on diagnostic algorithms and main multimodality imaging techniques. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs for cancer pain. We used the Delphi methodology to evaluate the opinions of clinicians on NSAIDs and paracetamol, with a specific focus on their safety profile. Consensus was reached on seven statements. A high level of consensus was reached regarding the use of NSAIDs and gastrointestinal, cardiovascular, and renal risk in patients taking low-dose aspirin and assessment of liver function during long-term treatment with paracetamol. Consensus was also reached that assessment and monitoring of eGFR are important in the elderly being administered NSAIDs. It was further agreed that NSAIDs can often play a key role in association with opioids in the treatment of cancer pain and that paracetamol is the analgesic of first choice for patients with mild chronic pain. When NSAIDs are administered in combination with steroids, it was agreed that the risk of gastrointestinal damage is increased since steroids delay the healing of ulcers and that paracetamol can be used during pregnancy and does not affect the health of the fetus. This Delphi study highlights that there is poor agreement on how these drugs are routinely prescribed. However, a consensus was reached for seven key statements and may represent a valid contribution to daily practice. [ABSTRACT FROM AUTHOR]

Background: The monoclonal antibody durvalumab, an immune‐checkpoint inhibitor (ICI) antiprogrammed death ligand 1 (PD‐L1), is available for unresectable stage III NSCLC patients as consolidation therapy following induction chemoradiotherapy, with very promising overall survival (OS) and progression‐free survial (PFS) results in registration trials. The purpose of this study was to provide policymakers with an estimate of the cost‐effectiveness of durvalumab in the treatment of non‐small cell lung cancer (NSCLC). Methods: The study developed a Markov model covering a 5‐year period to compare costs and outcomes of treating PD‐L1 positive patients with or without durvalumab. We conducted a series of sensitivity analyses (Tornado analysis and Monte Carlo simulation) by varying some parameters to assess the robustness of our model and identify the parameters with the greatest impact on cost‐effectiveness. Results: Prior to the release of durvalumab, the management of NSCLC over a 5‐year period cost €33 317 per patient, with an average life expectancy of 2.01 years. After the introduction of the drug, this increased to €37 317 per patient, with an average life expectancy of 2.13 years. Treatment with durvalumab led to an incremental cost‐effectiveness ratio (ICER) of €35 526 per year. OS is the variable that contributes the most to the variability of the ICER. Conclusions: The study observed that durvalumab is a cost‐effective treatment option for patients with unresectable stage III NSCLC. [ABSTRACT FROM AUTHOR]

Background: Enhanced recovery after surgery (ERAS) programs influence morbidity rates and length of stay after colorectal surgery (CRS), and may also impact major complications and anastomotic leakage rates. A prospective multicenter observational study to investigate the interactions between ERAS program adherence and early outcomes after elective CRS was carried out.Methods: Prospective enrolment of patients submitted to elective CRS with anastomosis in 18 months. Adherence to 21 items of ERAS program was measured upon explicit criteria in every case. After univariate analysis, independent predictors of primary endpoints [major morbidity (MM) and anastomotic leakage (AL) rates] were identified through logistic regression analyses including all significant variables, presenting odds ratios (OR).Results: Institutional ERAS protocol was declared by 27 out of 38 (71.0%) participating centers. Median overall adherence to ERAS program items was 71.4%. Among 3830 patients included in the study, MM and AL rates were 4.7% and 4.2%, respectively. MM rates were independently influenced by intra- and/or postoperative blood transfusions (OR 7.79, 95% CI 5.46-11.10; p < 0.0001) and standard anesthesia protocol (OR 0.68, 95% CI 0.48-0.96; p = 0.028). AL rates were independently influenced by male gender (OR 1.48, 95% CI 1.06-2.07; p = 0.021), intra- and/or postoperative blood transfusions (OR 4.29, 95% CI 2.93-6.50; p < 0.0001) and non-standard resections (OR 1.49, 95% CI 1.01-2.22; p = 0.049).Conclusions: This study disclosed wide room for improvement in compliance to several ERAS program items. It failed to detect any significant association between institutionalization and/or adherence rates to ERAS program with primary endpoints. These outcomes were independently influenced by gender, intra- and postoperative blood transfusions, non-standard resections, and standard anesthesia protocol. [ABSTRACT FROM AUTHOR]

The role of minimally invasive surgery in the treatment of transverse colon cancer is still controversial. The aim of this study is to investigate the advantages of a totally laparoscopic technique comparing open versus laparoscopic/robotic approach. Three hundred and eighty-eight patients with transverse colon cancer, treated with a segmental colon resection, were retrospectively analyzed. Demographic data, tumor stage, operative time, intraoperative complications, number of harvested lymph nodes and recovery outcomes were recorded. Recurrences and death were also evaluated during the follow-up. No differences were found between conventional and minimally invasive surgery, both for oncological long-term outcomes (recurrence rate p = 0.28; mortality p = 0.62) and postoperative complications (overall rate p = 0.43; anemia p = 0.78; nausea p = 0.68; infections p = 0.91; bleeding p = 0.62; anastomotic leak p = 0.55; ileus p = 0.75). Nevertheless, recovery outcomes showed statistically significant differences in favor of minimally invasive surgery in terms of time to first flatus (p = 0.001), tolerance to solid diet (p = 0.017), time to first mobilization (p = 0.001) and hospital stay (p = 0.004). Compared with laparoscopic approach, robotic surgery showed significantly better results for time to first flatus (p = 0.001), to first mobilization (p = 0.005) and tolerance to solid diet (p = 0.001). Finally, anastomosis evaluation confirmed the superiority of intracorporeal approach which showed significantly better results for time to first flatus (p = 0.001), to first mobilization (p = 0.003) and tolerance to solid diet (p = 0.001); moreover, we recorded a statistical difference in favor of intracorporeal approach for infection rate (p = 0.04), bleeding (p = 0.001) and anastomotic leak (p = 0.03). Minimally invasive approach is safe and effective as the conventional open surgery, with comparable oncological results but not negligible advantages in terms of recovery outcomes. Moreover, we demonstrated that robotic approach may be considered a valid option and an intracorporeal anastomosis should always be preferred. [ABSTRACT FROM AUTHOR]

Heavily doped semiconductors have emerged as low-loss and tunable materials for plasmonics at mid-infrared frequencies. We analyze the nonlinear optical response of free electrons and show how nonlinear optical phenomena associated with high electron concentration are influenced by the intrinsic properties of semiconductors, namely background permittivity and effective mass. We apply our recently developed hydrodynamic description that takes into account nonlinear contributions up to the third order, usually negligible for noble metals, to compare third-harmonic generation from InP, Ge, GaAs, Si, ITO and InSb. We show how free electron nonlinearities may be enhanced with a proper choice of the semiconductor. [ABSTRACT FROM AUTHOR]