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Cannabidiol (CBD) is one of the principal constituents of Cannabis Sativa with no psychoactive properties. CBD is a promising neuroprotective compound bearing anti-inflammatory and antioxidant properties. However, considering its low solubility, CBD delivery to the retina represents an unresolved issue. The first aim was to investigate the potential neuroprotective effects of CBD in an in vivo model of retinal excitotoxicity induced by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Rats underwent intravitreal co-injection of AMPA (42 nmol) and CBD (10 -4  M). The neuroprotective effect of CBD was investigated with histology and immunohistochemical evaluation of inflammatory and oxidative stress biomarkers. CBD reversed the AMPA-induced total retinal, inner nuclear layer and inner plexiform layer shrinkage and loss of amacrine cells. Moreover, CBD decreased the AMPA induced number of cleaved caspase-3, Iba-1 and nitrotyrosine (NT) positive cells. Based on this evidence, we developed a nanotechnological formulation of CBD to overcome critical issues related to its eye delivery. Particularly, nanostructured lipid carriers (NLC) loaded with CBD were prepared, optimized and characterized. Due to the optimal physicochemical characteristics, CBD-NLC3 has been selected and the in vitro release profile has been investigated. Additionally, CBD-NLC3 was topically administered to rats, and retinal CBD levels were determined. CBD-NLC3 formulation, after a single topical administration, efficiently delivered CBD in the retina (C max  = 98 ± 25.9 ng/mg; T max  = 60 min), showing a high translational value. In conclusion, these findings showed a good PD/PK profile of CBD warranting further pre-clinical and clinical evaluation of the new formulation for the treatment of retinal degenerative diseases., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The optimal management of acute ischemic stroke (AIS) in patients with oral anticoagulation (OA) is challenging. Our study aimed to analyze the clinical characteristics and outcome of AIS in patients with OA for nonvalvular atrial fibrillation (NVAF)., Methods: We retrospectively analyzed data on NVAF patients with AIS on direct oral anticoagulants (DOAC) or vitamin K antagonists (VKA) admitted to our Stroke Unit from 2017 to 2022. Ninety-day modified Rankin Scale (mRS), 90-day, and 12-month stroke recurrences were recorded., Results: A total of 169 patients (53.2% female, mean age 82.8±6.7 y), 117 (69.2%) on DOAC, and 52 on VKA (30.8%), were enrolled. Mean age, in-hospital mortality, and 90-day mRS ≥4 were significantly higher in VKA patients. 63.4% of VKA patients had subtherapeutic INR, whereas 47.1% of DOAC patients were on low-dose (14.2% off-label). Large vessel occlusion and embolic etiology were more frequent in VKA patients (34.6% vs. 26.4%, P =0.358; 92.3% vs. 74.3%, P =0.007, respectively), whereas lacunar strokes were more frequent in DOAC patients (19.8% vs. 12.2%, P =0.366). Among patients on VKA before AIS 86.4% were switched to DOAC, whereas a DOAC-to-VKA and a DOAC-to-DOAC switch were done in 25.4% and 11.7%, respectively. Stroke recurrence occurred in 6.4% of patients at 90 days and 10.7% at 12 months. Anticoagulant switching was not associated with stroke recurrences., Conclusions: In our study, nonembolic etiology was more frequent in DOAC patients and anticoagulant switching did not reduce the risk of stroke recurrence. Prospective multicentric studies are warranted., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The benzoxazole is one of the most widely exploited heterocycles in drug discovery. Natural occurring and synthetic benzoxazoles show a broad range of biological activities. Many benzoxazoles are available for treating several diseases, and, to date, a few are in clinical trials. Moreover, an ever-increasing number of benzoxazole derivatives are under investigation in the early drug discovery phase and as potential hit or lead compounds. This perspective is an attempt to thoroughly review the rational design, the structure-activity relationship, and the biological activity of the most notable benzoxazoles developed during the past 5 years (period 2019-to date) in cancers, neurological disorders, and inflammation. We also briefly overviewed each target and its role in the disease. The huge amount of work examined suggests the great potential of the scaffold and the high interest of the scientific community in novel biologically active compounds containing the benzoxazole core., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Psychosis is a characterizing feature of many mental disorders that dramatically affects human thoughts and perceptions, influencing the ability to distinguish between what is real and what is not. Both genetic and environmental factors, such as stressful events or drug use, play a pivotal role in the development of symptomatology and therefore changes in the epigenome may be of relevance in modeling a psychotic phenotype. According to the well-documented dysregulation of endocannabinoid and dopaminergic system genes in schizophrenia, we investigated DNA methylation cannabinoid type 1 receptor (CNR1) and dopamine D2 receptor (DRD2) genes in saliva samples from psychotic subjects using pyrosequencing. The epigenetic mark was significantly higher and directly correlated for both genes in psychotic subjects compared to healthy controls. We also showed that these DNA methylation levels were lower in psychotic subjects reporting current delta-9-tetrahydrocannabinol (THC) consumption, a well-known risk factor for developing psychosis throughout the lifespan, resembling those of controls at least for the DRD2 gene. Overall, our data confirm the key role of CNR1 and DRD2 gene regulation in psychosis and suggest DNA methylation levels at specific CpG sites as potential biomarkers, but just in those psychotic subjects not consuming THC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The abundance and distribution of tumor-infiltrating lymphocytes (TILs) as well as that of other components of the tumor microenvironment is of particular importance for predicting response to immunotherapy in lung cancer (LC). We describe here a pilot study employing artificial intelligence (AI) in the assessment of TILs and other cell populations, intending to reduce the inter- or intra-observer variability that commonly characterizes this evaluation., Design: We developed a machine learning-based classifier to detect tumor, immune, and stromal cells on hematoxylin and eosin-stained sections, using the open-source framework QuPath . We evaluated the quantity of the aforementioned three cell populations among 37 LC whole slide images regions of interest, comparing the assessments made by five pathologists, both before and after using graphical predictions made by AI, for a total of 1110 quantitative measurements., Results: Our findings indicate noteworthy variations in score distribution among pathologists and between individual pathologists and AI. The AI-guided pathologist's evaluations resulted in reduction of significant discrepancies across pathologists: three comparisons showed a loss of significance ( p  > 0.05), whereas other four showed a reduction in significance ( p  > 0.01)., Conclusions: We show that employing a machine learning approach in cell population quantification reduces inter- and intra-observer variability, improving reproducibility and facilitating its use in further validation studies., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matteo Pallocca reports a relationship with Dexma srl that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (© 2024 The Authors.)

Background: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated., Methods: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed., Results: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats., Conclusions: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia., (© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

In recent years, medicine has undergone profound changes, strongly entering a new phase defined as the "era of precision medicine". In this context, patient clinical management involves various scientific approaches that allow for a comprehensive pathology evaluation: from preventive processes (where applicable) to genetic and diagnostic studies. In this scenario, biobanks play an important role and, over the years, have gained increasing prestige, moving from small deposits to large collections of samples of various natures. Disease-oriented biobanks are rapidly developing as they provide useful information for the management of complex diseases, such as melanoma. Indeed, melanoma, given its highly heterogeneous characteristics, is one of the oncologic diseases with the greatest clinical and therapeutic management complexity. So, the possibility of extrapolating tissue, genetic and imaging data from dedicated biobanks could result in more selective study approaches. In this review, we specifically analyze the several biobank types to evaluate their role in technology development, patient monitoring and research of new biomarkers, especially in the melanoma context.

Background: During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D., Methods: aHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC) Trastuzumab-emtansine (T-DM1)., Results: As expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI [210-354] vs [56-209], log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI [255-444] vs [45-232], log-rank test p=0.009)., Conclusions: HER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors., Trial Registration: NCT05735392 retrospectively registered on January 31, 2023 https://www., Clinicaltrials: gov/search?term=NCT05735392., (© 2024. The Author(s).)

Scientific literature supports the evidence that cancer stem cells (CSCs) retain inside low reactive oxygen species (ROS) levels and are, therefore, less susceptible to cell death, including ferroptosis, a type of cell death dependent on iron-driven lipid peroxidation. A collection of lung adenocarcinoma (LUAD) primary cell lines derived from malignant pleural effusions (MPEs) of patients was used to obtain 3D spheroids enriched for stem-like properties. We observed that the ferroptosis inducer RSL3 triggered lipid peroxidation and cell death in LUAD cells when grown in 2D conditions; however, when grown in 3D conditions, all cell lines underwent a phenotypic switch, exhibiting substantial resistance to RSL3 and, therefore, protection against ferroptotic cell death. Interestingly, this phenomenon was reversed by disrupting 3D cells and growing them back in adherence, supporting the idea of CSCs plasticity, which holds that cancer cells have the dynamic ability to transition between a CSC state and a non-CSC state. Molecular analyses showed that ferroptosis resistance in 3D spheroids correlated with an increased expression of antioxidant genes and high levels of proteins involved in iron storage and export, indicating protection against oxidative stress and low availability of iron for the initiation of ferroptosis. Moreover, transcriptomic analyses highlighted a novel subset of genes commonly modulated in 3D spheroids and potentially capable of driving ferroptosis protection in LUAD-CSCs, thus allowing to better understand the mechanisms of CSC-mediated drug resistance in tumors., (© 2024. The Author(s).)

Background: Few data are available about the durability of the response, the induction of neutralizing antibodies, and the cellular response upon the third dose of the anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in hemato-oncological patients., Objective: To investigate the antibody and cellular response to the BNT162b2 vaccine in patients with hematological malignancy., Methods: We measured SARS-CoV-2 anti-spike antibodies, anti- Omicron neutralizing antibodies, and T-cell responses 1 month after the third dose of vaccine in 93 fragile patients with hematological malignancy (FHM), 51 fragile not oncological subjects (FNO) aged 80-92, and 47 employees of the hospital (healthcare workers, (HW), aged 23-66 years. Blood samples were collected at day 0 (T0), 21 (T1), 35 (T2), 84 (T3), 168 (T4), 351 (T pre-3D), and 381 (T post-3D) after the first dose of vaccine. Serum IgG antibodies against S1/S2 antigens of SARS-CoV-2 spike protein were measured at every time point. Neutralizing antibodies were measured at T2, T3 (anti-Alpha), T4 (anti-Delta), and T post-3D (anti- Omicron ). T cell response was assessed at T post-3D., Results: An increase in anti-S1/S2 antigen antibodies compared to T0 was observed in the three groups at T post-3D. After the third vaccine dose, the median antibody level of FHM subjects was higher than after the second dose and above the putative protection threshold, although lower than in the other groups. The neutralizing activity of antibodies against the Omicron variant of the virus was tested at T2 and T post-3D. 42.3% of FHM, 80,0% of FNO, and 90,0% of HW had anti- Omicron neutralizing antibodies at T post-3D. To get more insight into the breadth of antibody responses, we analyzed neutralizing capacity against BA.4/BA.5, BF.7, BQ.1, XBB.1.5 since also for the Omicron variants, different mutations have been reported especially for the spike protein. The memory T-cell response was lower in FHM than in FNO and HW cohorts. Data on breakthrough infections and deaths suggested that the positivity threshold of the test is protective after the third dose of the vaccine in all cohorts., Conclusion: FHM have a relevant response to the BNT162b2 vaccine, with increasing antibody levels after the third dose coupled with, although low, a T-cell response. FHM need repeated vaccine doses to attain a protective immunological response., Competing Interests: Author MC is employed in Neomatrix, Rome, Italy. EPi is employed in Takis, Rome, Italy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Laquintana, Mottini, Marchesi, Marcozzi, Terrenato, Sperandio, de Latouliere, Carrieri, Pimpinelli, Pontone, Pellini, Campo, Conti, Accetta, Mandoj, Petrone, Di Bella, Vujovic, Morrone, Compagnone, Principato, Pinto, Papa, Falcucci, La Malfa, Pallocca, De Marco, Piaggio, Ciliberto, Mengarelli and di Martino.)

Since the discovery of graphene, there has been a wide range of the literature dealing with its versatile structure and easy binding of biomolecules as well as its large loading capacity. In the emerging field of immunotherapy, graphene and its derivatives have potential uses as drug delivery platforms directly into tumour sites or as adjuvants in cancer vaccines, as they are internalized by monocytes which in turn may activate adaptive anti-tumoral immune responses. In this study, we expose cells of the innate immune system and a human acute monocytic leukemia cell line (THP-1) to low doses of small-sized GO nanosheets functionalized with bovine serum albumin (BSA) and fluorescein isothiocyanate (FITC), to study their acute response after internalization. We show by flow cytometry, uptake in cells of GO-BSA-FITC reaches 80% and cell viability and ROS production are both unaffected by exposure to nanoparticles. On the contrary, GO-BSA nanosheets seem to have an inhibitory effect on ROS production, probably due to their antioxidant properties. We also provided results on chemotaxis of macrophages derived from peripheral blood monocytes treated with GO-BSA. In conclusion, we showed the size of nanosheets, the concentration used and the degree of functionalization were important factors for biocompatibility of GO in immune cells. Its low cytotoxicity and high adaptability to the cells of the innate immune system make it a good candidate for deployment in immunotherapy, in particular for delivering protein antigens to monocytes which activate adaptive immunity., Competing Interests: The authors declare no conflict of interest.

Background: Lysine demethylase enzymes (KDMs) are an emerging class of therapeutic targets, that catalyse the removal of methyl marks from histone lysine residues regulating chromatin structure and gene expression. KDM4A isoform plays an important role in the epigenetic dysregulation in various cancers and is linked to aggressive disease and poor clinical outcomes. Despite several efforts, the KDM4 family lacks successful specific molecular inhibitors., Results: Herein, starting from a structure-based fragments virtual screening campaign we developed a synergic framework as a guide to rationally design efficient KDM4A inhibitors. Commercial libraries were used to create a fragments collection and perform a virtual screening campaign combining docking and pharmacophore approaches. The most promising compounds were tested in-vitro by a Homogeneous Time-Resolved Fluorescence-based assay developed for identifying selective substrate-competitive inhibitors by means of inhibition of H3K9me3 peptide demethylation. 2-(methylcarbamoyl)isonicotinic acid was identified as a preliminary active fragment, displaying inhibition of KDM4A enzymatic activity. Its chemical exploration was deeply investigated by computational and experimental approaches which allowed a rational fragment growing process. The in-silico studies guided the development of derivatives designed as expansion of the primary fragment hit and provided further knowledge on the structure-activity relationship., Conclusions: Our study describes useful insights into key ligand-KDM4A protein interaction and provides structural features for the development of successful selective KDM4A inhibitors., (© 2023. The Author(s).)

Primary mitochondrial diseases (PMDs) are complex group of metabolic disorders caused by genetically determined impairment of the mitochondrial oxidative phosphorylation (OXPHOS). The unique features of mitochondrial genetics and the pivotal role of mitochondria in cell biology explain the phenotypical heterogeneity of primary mitochondrial diseases and the resulting diagnostic challenges that follow. Some peculiar features ("red flags") may indicate a primary mitochondrial disease, helping the physician to orient in this diagnostic maze. In this narrative review, we aimed to outline the features of the most common mitochondrial red flags offering a general overview on the topic that could help physicians to untangle mitochondrial medicine complexity.

Upstanding civic action is central to individual and community well-being, particularly when communities comprise rich and diverse membership. However, not all groups in society have the same opportunities and resources to volunteer. This is particularly true for South Asian people, who are often reported to be less likely to volunteer. Research into the experience and meanings that this ethnic group attributes to volunteering has been exceptionally scarce. Informed by a community psychology perspective, this qualitative study conducted nine semistructured interviews with British South Asians involved in formal volunteering activities. The aim was to explore their personal experiences and motivations regarding volunteering for their community of belonging. Results from reflexive thematic analysis were grouped under three themes. These were (1) volunteering cultivated individual well-being, (2) South Asians who volunteer often experience social injustice and marginalisation and (3) volunteering for South Asians is intrinsically tied to religious and cultural motivations. British South Asians faced personal and social obstacles in accessing fundamental health and social care in their communities of belonging. Religion, and community social capital were positive volunteering strategies for British South Asians. Positive impacts of well-being included becoming closer to faith and increased sense of meaning/purpose and recognising of individual strengths. These findings offer valuable insights and recommendations for community organisations and governmental bodies to better promote volunteering for ethnic minorities. We suggest the adoption of cultural and religious sensitivity, along with strategies to remove barriers in access to opportunities and support for volunteering., (© 2023 The Authors. Journal of Community Psychology published by Wiley Periodicals LLC.)

Study Design: Systematic Review., Objectives: The aim of this systematic review is to evaluate the efficacy of non-invasive procedures in relieving chronic pain due to Failed Back Surgery Syndrome (FBSS)., Methods: Since patients who suffered from FBBS are often non-responders to analgesics, we compared Visual Analogical Scale for low back and leg pain, Oswestry Disability Index, trial success rate, adverse events and complications between conservative treatment groups and control groups., Results: The included studies were 15. Spinal Cord Stimulation (SCS) was performed in 11 trials; 4 studies assessed the efficacy of different epidural injections; one study evaluated repetitive Transcranial Magnetic Stimulation. All the studies reported back and leg pain relief after treatment with SCS, with a significant superiority in high frequences (HFS) group, compared to low frequences (LFS) group. Moreover, disability decreased with each non-invasive treatment evaluated. Epidural injections of steroids and hyaluronidase have shown controversial results. Adverse events were described in 7 studies: lead migration, hardware-related events, infection and incisional pain were the most reported. Finally, trial success rate showed better outcomes for HFS., Conclusions: Our systematic review highlights the efficacy of conservative treatments in FBSS patients, with an improvement in pain scores and a decrease in disability index, especially after SCS with HFS. However, due to the lack of homogeneity among trials and population characteristics, further studies are needed to confirm the effectiveness of non-invasive interventions in patients affected by FBSS.

Background: Few data exists on predictive factors of hemorrhagic transformation (HT) in real-world acute ischemic stroke patients. The aims of this study were: (i) to identify predictive variables of HT (ii) to develop a score for predicting HT., Methods: We retrospectively analyzed the clinical, radiographic, and laboratory data of patients with acute ischemic stroke consecutively admitted to our Stroke Unit along two years. Patients with HT were compared with those without HT. A multivariate logistic regression analysis was performed to identify independent predictors of HT on CT scan at 24 hours to develop a practical score., Results: The study population consisted of 564 patients with mean age 77.5±11.8 years. Fifty-two patients (9.2%) showed HT on brain CT at 24 hours (4.9% symptomatic). NIHSS score ≥8 at Stroke Unit admission (3 points), cardioembolic etiology (2 points), acute revascularization by systemic thrombolysis and/or mechanical thrombectomy (1 point), history of previous TIA/stroke (1 point), and major vessel occlusion (1 point) were found independent risk factors of HT and were included in the score (Hemorrhagic Transformation Empoli score (HTE)). The predictive power of HTE score was good with an AUC of 0.785 (95% CI: 0.749-0.818). Compared with 5 HT predictive scores proposed in the literature (THRIVE, SPAN-100, MSS, GRASPS, SITS-SIC), the HTE score significantly better predicted HT., Conclusions: NIHSS score ≥8 at Stroke Unit admission, cardioembolism, urgent revascularization, previous TIA/stroke, and major vessel occlusion were independent predictors of HT. The HTE score has a good predictive power for HT. Prospective studies are warranted., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To evaluate the neuroprotective effect of the topical ocular administration of fluoxetine (FLX) in a mouse model of acute retinal damage., Methods: Ocular ischemia/reperfusion (I/R) injury in C57BL/6J mice was used to elicit retinal damage. Mice were divided into three groups: control group, I/R group, and I/R group treated with topical FLX. A pattern electroretinogram (PERG) was used as a sensitive measure of retinal ganglion cell (RGC) function. Finally, we analyzed the retinal mRNA expression of inflammatory markers (IL-6, TNF-α, Iba-1, IL-1β, and S100β) through Digital Droplet PCR., Results: PERG amplitude values were significantly ( p < 0.05) higher in the I/R-FLX group compared to the I/R group, whereas PERG latency values were significantly ( p < 0.05) reduced in I/R-FLX-treated mice compared to the I/R group. Retinal inflammatory markers increased significantly ( p < 0.05) after I/R injury. FLX treatment was able to significantly ( p < 0.05) attenuate the expression of inflammatory markers after I/R damage., Conclusions: Topical treatment with FLX was effective in counteracting the damage of RGCs and preserving retinal function. Moreover, FLX treatment attenuates the production of pro-inflammatory molecules elicited by retinal I/R damage. Further studies need to be performed to support the use of FLX as neuroprotective agent in retinal degenerative diseases.

Adolescent exposure to cannabinoids as a postnatal environmental insult may increase the risk of psychosis in subjects exposed to perinatal insult, as suggested by the two-hit hypothesis of schizophrenia. Here, we hypothesized that peripubertal Δ 9 -tetrahydrocannabinol (aTHC) may affect the impact of prenatal methylazoxymethanol acetate (MAM) or perinatal THC (pTHC) exposure in adult rats. We found that MAM and pTHC-exposed rats, when compared to the control group (CNT), were characterized by adult phenotype relevant to schizophrenia, including social withdrawal and cognitive impairment, as revealed by social interaction test and novel object recognition test, respectively. At the molecular level, we observed an increase in cannabinoid CB1 receptor ( Cnr1 ) and/or dopamine D2/D3 receptor ( Drd2, Drd3 ) gene expression in the prefrontal cortex of adult MAM or pTHC-exposed rats, which we attributed to changes in DNA methylation at key regulatory gene regions. Interestingly, aTHC treatment significantly impaired social behavior, but not cognitive performance in CNT groups. In pTHC rats, aTHC did not exacerbate the altered phenotype nor dopaminergic signaling, while it reversed cognitive deficit in MAM rats by modulating Drd2 and Drd3 gene expression. In conclusion, our results suggest that the effects of peripubertal THC exposure may depend on individual differences related to dopaminergic neurotransmission.

Background: In selective internal radiation therapy, 99m Tc SPECT images are used to optimize patient treatment planning, but they are affected by respiratory motion. In this study, we evaluated on patient data the dosimetric impact of motion-compensated SPECT reconstruction on several volumes of interest (VOI), on the tumor-to-normal liver (TN) ratio and on the activity to be injected., Methods: Twenty-nine patients with liver cancer or hepatic metastases treated by radioembolization were included in this study. The biodistribution of 90 Y is assumed to be the same as that of 99m Tc when predictive dosimetry is implemented. A total of 31 99m Tc SPECT images were acquired and reconstructed with two methods: conventional OSEM (3D) and motion-compensated OSEM (3Dcomp). Seven VOI (liver, lungs, tumors, perfused liver, hepatic reserve, healthy perfused liver and healthy liver) were delineated on the CT or obtained by thresholding SPECT images followed by Boolean operations. Absorbed doses were calculated for each reconstruction using Monte Carlo simulations. Percentages of dose difference (PDD) between 3Dcomp and 3D reconstructions were estimated as well as the relative differences for TN ratio and activities to be injected. The amplitude of movement was determined with local rigid registration of the liver between the 3Dcomp reconstructions of the extreme phases of breathing., Results: The mean amplitude of the liver was 9.5 ± 2.7 mm. Medians of PDD were closed to zero for all VOI except for lungs (6.4%) which means that the motion compensation overestimates the absorbed dose to the lungs compared to the 3D reconstruction. The smallest lesions had higher PDD than the largest ones. Between 3D and 3Dcomp reconstructions, means of differences in lung dose and TN ratio were not statistically significant, but in some cases these differences exceed 1 Gy (4/31) and 8% (2/31). The absolute differences in activity were on average 3.1% ± 5.1% and can reach 22.8%., Conclusion: The correction of respiratory motion mainly impacts the lung and tumor doses but only for some patients. The largest dose differences are observed for the smallest lesions., (© 2023. The Author(s).)

The etiopathogenesis of mental disorders is not fully understood and accumulating evidence support that clinical symptomatology cannot be assigned to a single gene mutation, but it involves several genetic factors. More specifically, a tight association between genes and environmental risk factors, which could be mediated by epigenetic mechanisms, may play a role in the development of mental disorders. Several data suggest that epigenetic modifications such as DNA methylation, post-translational histone modification and interference of microRNA (miRNA) or long non-coding RNA (lncRNA) may modify the severity of the disease and the outcome of the therapy. Indeed, the study of these mechanisms may help to identify patients particularly vulnerable to mental disorders and may have potential utility as biomarkers to facilitate diagnosis and treatment of psychiatric disorders. This article summarizes the most relevant preclinical and human data showing how epigenetic modifications can be central to the therapeutic efficacy of antidepressant and/or antipsychotic agents, as possible predictor of drugs response., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Whereas the behavioral and health sciences have been mainly concerned with the private good, there is an urgent need to understand and foster the collective good. Without a coherent framework for the common good, it will be extremely difficult to prevent and manage crises such as pandemics, illness, climate change, poverty, discrimination, injustice, and inequality, all of which affects marginalized populations disproportionally. While frameworks for personal well-being abound in psychology, psychiatry, counseling, and social work, conceptualizations of collective well-being are scarce. Our search for foundations of the common good resulted in the identification of three psychosocial goods: mattering, wellness, and fairness. There are several reasons for choosing them, including the fact that they concurrently advance personal, relational, and collective value. In addition, they represent basic human motivations, have considerable explanatory power, exist at multiple ecological levels, and have significant transformative potential. The complementary nature of the three goods is illustrated in an interactional model. Based on empirical evidence, we suggest that conditions of justice lead to experiences of mattering, which, in turn, enhance wellness. Challenges and opportunities afforded by the model at the intrapersonal, interpersonal, occupational, communal, national, and global levels are presented. The proposed psychosocial goods are used to formulate a culture for the common good in which we balance the right with the responsibility to feel valued and add value, to self and others, in order to promote not just wellness but also fairness. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Rationale: Metastatic melanoma is the most aggressive and dangerous form of skin cancer. The introduction of immunotherapy with Immune checkpoint Inhibitors (ICI) and of targeted therapy with BRAF and MEK inhibitors for BRAF mutated melanoma, has greatly improved the clinical outcome of these patients. Nevertheless, response to therapy remains highly variable and the development of drug resistance continues to be a daunting challenge. Within this context there is a need to develop diagnostic tools capable of predicting response or resistance to therapy in order to select the best therapeutic approach. Over the years, accumulating evidence brought to light the role of microRNAs (miRNAs) as disease biomarkers. Methods: In particular, the detection of miRNAs in whole blood or specific blood components such as serum or plasma, allows these molecules to be good candidates for diagnosis, prognosis and for monitoring response to anticancer therapy. In this paper, we evaluated circulating basal levels of 6 previously identified miRNAs in serum samples of 70 BRAF-mutant melanoma patients before starting targeted therapy. Results: Results show that the circulating levels of the oncosuppressor miR-579-3p and of the oncomiR miR-4488 are able to predict progression free survival (PFS) but not overall survival (OS). Most importantly, we observed that the best predictor of disease outcome is represented by the ratio of circulating miR-4488 vs. miR-579-3p (miRatio). Finally, the combination of the Lactate dehydrogenase (LDH) blood levels with the two circulating miRNAs alone or together did not produce any improvement in predicting PFS indicating that miR-579-3p and miR-4488 are independent predictors of PFS as compared to LDH. Conclusions: All together these data underscored the relevance of circulating miRNAs as suitable tools to predict therapy response in melanoma and maybe further developed as companion diagnostics in the clinic., Competing Interests: Competing Interests: All the authors declare no conflict of interest with the exception of P.A.A. Paolo A. Ascierto has/had a consultant/advisory role for Bristol MyersSquibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. Travel support by Pfizer. The funders of this study had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (© The author(s).)

Theoretical arguments and empirical evidence have been provided in the literature for the role of fairness in wellness. In this paper, we explore the role of two potential mediating variables: autonomous human choice and social capital. Using aggregated panel data across countries belonging to the Organisation for Economic Co-operation and Development (OECD), we compared the OECD Social Justice Index (SJI) with data on life satisfaction to test whether fairness has direct and indirect effects on wellness. Results from a series of Manifest Path Analyses with time as fixed effect, support the hypothesis that the OECD SJI is directly linked to country-level life satisfaction, additionally revealing that its indirect effect operates primarily through people's autonomous choices in life and their country's level of social capital. Our results contribute to two distinct bodies of knowledge. With respect to community psychology, the findings offer empirical evidence for the synergistic effect of personal, relational, and collective factors in well-being. With respect to the impact of economic inequality on wellness, we extend the literature by using social justice as a more comprehensive measure. Limitations and recommendations for future studies are discussed., (© 2022 The Authors. Journal of Community Psychology published by Wiley Periodicals LLC.)

Recent decades have witnessed a growing number of states around the world relying on border control measures, such as immigration detention, to govern human mobility and control the movements of those classified as "unauthorised non-citizens." In response to this, an increasing number of scholars from several disciplines, including psychologists, have begun to examine this phenomenon. In spite of the widespread concerns raised, few studies have been conducted inside immigration detention sites, primarily due to difficulties in gaining access. This body of research becomes even scanter when it comes to the experiences of detained women. This study is the first of its kind to have surveyed 93 women confined in an Italian immigration detention facility. A partial mediation model with latent variables was tested through partial least structural equation modelling (PLS-SEM). The findings revealed the negative impact that unfair immigration procedures have on detained women's human dignity, which in turn negatively affects their self-rated physical and mental health. Overall, our study sheds light on the dehumanisation and damage to human dignity that immigration detention entails, as well as its negative impact on the health of those affected. This evidence reinforces the image of these institutions as sites of persistent injustice, while stressing the need to envision alternative justice-oriented forms to address human mobility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Esposito, Di Martino, Briozzo, Arcidiacono and Ornelas.)

Background: In 2014, the European Clinical Trials Regulation was drawn up by the European Commission to replace the Clinical Trials Directive. The new Regulation aims to solve the shortcomings revealed by the Directive, such as extensive timelines and high bureaucratic costs, while increasing standards for safety and transparency of clinical trials. Importantly, the Regulation also points at harmonizing procedures among European Member States. From January 31st, 2022, it will be possible to submit clinical studies through a new portal, namely the Clinical Trials Information System. Since not complying to the Regulation implies not participating in clinical trials, many European countries underwent changes in national documents and related procedures. In The Netherlands, the Site Suitability Declaration, a document necessary to ascertain the adequacy of a site to perform a trial, was reviewed., Methods: In our research, we investigated the status of the VGO implementation during a transition period among different stakeholders involved in the start-up process through a validated questionnaire and subsequent semi-structured interviews., Results: This project showed a slow-paced implementation, linked to communication and organizational challenges but also to a negative approach towards the change. Nevertheless, some stakeholders expressed constructive feedback as well, indicating the VGO as an upgrade. The latter was mainly achieved through establishing a trustful relationship with other stakeholders, undergoing additional adjustments, and having a positive mindset., Conclusions: This research pointed at a still too scarce collaboration between stakeholders, who should rather actively contribute to achieve the implementation goal., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

The use of peptides as therapeutics has often been associated with several drawbacks such as poor absorption, low stability to proteolytic digestion, and fast clearance. Peptidomimetics are developed by modifications of native peptides with the aim of obtaining molecules that are more suitable for clinical development and, for this reason, are widely used as tools in medicinal chemistry programs. The effort to disclose innovative peptidomimetic therapies is recurrent and constantly evolving as demonstrated by the new lead compounds in clinical trials. Synthetic strategies for the development of peptidomimetics have also been implemented with time. This perspective highlights some of the most recent efforts for the design and synthesis of peptidomimetic agents together with their biological evaluation toward a panel of targets.

Background: Immune checkpoint inhibitors are still unable to provide clinical benefit to the large majority of non-small cell lung cancer (NSCLC) patients. A deeper characterization of the tumor immune microenvironment (TIME) is expected to shed light on the mechanisms of cancer immune evasion and resistance to immunotherapy. Here, we exploited malignant pleural effusions (MPEs) from lung adenocarcinoma (LUAD) patients as a model system to decipher TIME in metastatic NSCLC., Methods: Mononuclear cells from MPEs (PEMC) and peripheral blood (PBMC), cell free pleural fluid and/or plasma were collected from a total of 24 LUAD patients and 12 healthy donors. Bulk-RNA sequencing was performed on total RNA extracted from PEMC and matched PBMC. The DEseq2 Bioconductor package was used to perform differential expression analysis and CIBERSORTx for the regression-based immune deconvolution of bulk gene expression data. Cytokinome analysis of cell-free pleural fluid and plasma samples was performed using a 48-Plex Assay panel. THP-1 monocytic cells were used to assess macrophage polarization. Survival analyses on NSCLC patients were performed using KM Plotter (LUAD, N=672; lung squamous cell carcinoma, N=271)., Results: Transcriptomic analysis of immune cells and cytokinome analysis of soluble factors in the pleural fluid depicted MPEs as a metastatic niche in which all the components required for an effective antitumor response are present, but conscripted in a wound-healing, proinflammatory and tumor-supportive mode. The bioinformatic deconvolution analysis revealed an immune landscape dominated by myeloid subsets with the prevalence of monocytes, protumoral macrophages and activated mast cells. Focusing on macrophages we identified an MPEs-distinctive signature associated with worse clinical outcome in LUAD patients., Conclusions: Our study reports for the first time a wide characterization of MPEs LUAD microenvironment, highlighting the importance of specific components of the myeloid compartment and opens new perspectives for the rational design of new therapies for metastatic NSCLC., Competing Interests: Competing interests: All the authors with the exception of LA have nothing to disclose. LA is an employee of Takis srl., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim of this study is to present a short form of the I COPPE scale of multidimensional well-being. We conducted two studies, which include four samples collected across three countries, namely United States, Argentina, and Italy. In the pilot study we tested during the data analysis phase whether it was feasible to reduce the full I COPPE scale by omitting the items dealing with past well-being. Prompted by the positive results of the pilot study, we launched a final validation study with a sample of 2682 Italian people who completed the I COPPE scale short form, which is designed without items referring to past well-being. Results from a series of confirmatory factor analyses show that the I COPPE scale short form presents acceptable levels of construct validity and reliability. Moreover, the 7-factor correlated-trait model proved to be the best fit for the data. We discuss advantaged of using the I COPPE scale short form along with limitations and future recommendations., (© 2021 The Authors. Journal of Community Psychology Published by Wiley Periodicals LLC.)

The human heart has limited regenerative capacity. Therefore, patients often progress to heart failure after ischemic injury, despite advances in reperfusion therapies generally decreasing mortality. Depending on its glycosylation state, Follistatin-like 1 (FSTL1) has been shown to increase cardiomyocyte (CM) proliferation, decrease CM apoptosis, and prevent cardiac rupture in animal models of ischemic heart disease. To explore its therapeutic potential, we used a human in vitro model of cardiac ischemic injury with human induced pluripotent stem cell-derived CMs (iPSC-CMs) and assessed regenerative effects of two differently glycosylated variants of human FSTL1. Furthermore, we investigated the FSTL1-mediated interplay between human cardiac fibroblasts (cFBs) and iPSC-CMs in hypoxia. Both FSTL1 variants increased viability, while only hypo-glycosylated FSTL1 increased CM proliferation post-hypoxia. Human fetal cardiac fibroblasts (fcFBs) expressed and secreted FSTL1 under normoxic conditions, while FSTL1 secretion increased by iPSC-cFBs upon hypoxia but decreased in iPSC-CMs. Co-culture of iPSC-CMs and cFBs increased FSTL1 secretion compared with cFB mono-culture. Taken together, we confirm that FSTL1 induces iPSC-CM proliferation in a human cardiac in vitro hypoxia damage model. Furthermore, we show hypoxia-related FSTL1 secretion by human cFBs and indications for FSTL1-mediated intercellular communication between cardiac cell types in response to hypoxic conditions., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of Sprague-Dawley rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produces long-lasting behavioral alterations such as social withdrawal and cognitive impairment in adulthood, mimicking a schizophrenia-like phenotype. These abnormalities were preceded at neonatal age both by the delayed appearance of neonatal reflexes, an index of impaired brain maturation, and by higher 2-arachidonoylglycerol (2-AG) brain levels. Schizophrenia-like deficits were reversed by early treatment [from postnatal day (PND) 2 to PND 8] with the CB1 antagonist/inverse agonist AM251 (0.5 mg/kg/day). By contrast, early CB1 blockade affected the behavioral performance of control rats which was paralleled by enhanced 2-AG content in the prefrontal cortex (PFC). These results suggest that prenatal MAM insult leads to premorbid anomalies at neonatal age via altered tone of the endocannabinoid system, which may be considered as an early marker preceding the development of schizophrenia-like alterations in adulthood.

The Identification of reliable Biomarkers able to predict the outcome after nephrectomy of patients with clear cell renal cell carcinoma (ccRCC) is an unmet need. The gene expression analysis in tumor tissues represents a promising tool for better stratification of ccRCC subtypes and patients' evaluation., Methods: In our study we retrospectively analyzed using Next-Generation expression analysis (NanoString), the expression of a gene panel in tumor tissue from 46 consecutive patients treated with nephrectomy for non-metastatic ccRCC at two Italian Oncological Centres. Significant differences in expression levels of selected genes was sought. Additionally, we performed a univariate and a multivariate analysis on overall survival according to Cox regression model., Results: A 17-gene expression signature of patients with a recurrence-free survival (RFS) < 1 year (unfavorable genomic signature (UGS)) and of patients with a RFS > 5 years (favorable genomic signature (FGS)) was identified and resulted in being significantly correlated with overall survival of the patients included in this analysis (HR 51.37, p < 0.0001)., Conclusions: The identified Genomic Signatures may serve as potential biomarkers for prognosis prediction of non-metastatic RCC and could drive both follow-up and treatment personalization in RCC management.

The recent shift in socio-political debates and growing liberalization of Cannabis use across the globe has raised concern regarding its impact on vulnerable populations such as adolescents. Concurrent with declining perception of Cannabis harms, more adolescents are using it daily in several countries and consuming marijuana strains with high content of psychotropic delta (9)-tetrahydrocannabinol (THC). These dual, related trends seem to facilitate the development of compromised social and cognitive performance at adulthood, which are described in preclinical and human studies. Cannabis exerts its effects via altering signalling within the endocannabinoid system (ECS), which modulates the stress circuitry during the neurodevelopment. In this context early interventions appear to circumvent the emergence of adult neurodevelopmental deficits. Accordingly, Cannabis sativa second-most abundant compound, cannabidiol (CBD), emerges as a potential therapeutic agent to treat neuropsychiatric disorders. We first focus on human and preclinical studies on the long-term effects induced by adolescent THC exposure as a "critical window" of enhanced neurophysiological vulnerability, which could be involved in the pathophysiology of schizophrenia and related primary psychotic disorders. Then, we focus on adolescence as a "window of opportunity" for early pharmacological treatment, as novel risk reduction strategy for neurodevelopmental disorders. Thus, we review current preclinical and clinical evidence regarding the efficacy of CBD in terms of positive, negative and cognitive symptoms treatment, safety profile, and molecular targets., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Research has suggested a fundamental connection between fairness and well-being at the individual, relational, and societal levels. Mattering is a multidimensional construct consisting of feeling valued by, and adding value to, self and others. Prior studies have attempted to connect mattering to both fairness and a variety of well-being outcomes. Based on these findings, we hypothesize that mattering acts as a mediator between fairness and well-being. This hypothesis was tested through Covariance-Based Structural Equation Modeling (CB-SEM) using multidimensional measures of fairness, mattering, and well-being. Results from a Latent Path Analysis conducted on a representative sample of 1,051U.S. adults provide support to our hypothesis by revealing a strong direct predictive effect of mattering onto well-being and a strong indirect effect of fairness onto well-being through mattering. Results also show that mattering is likely to fully mediate the relationship between fairness and multiple domains of well-being, except in one case, namely, economic well-being. These findings illustrate the value of a focus on mattering to understand the relationship between fairness and well-being and to provide future directions for theory, research, and practice. Theoretical implications for the experience of citizenship and participation, along with cross-cultural considerations, are also discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Scarpa, Di Martino and Prilleltensky.)

Clinical outcomes of COVID-19 patients are worsened by the presence of co-morbidities, especially cancer leading to elevated mortality rates. SARS-CoV-2 infection is known to alter immune system homeostasis. Whether cancer patients developing COVID-19 present alterations of immune functions which might contribute to worse outcomes have so far been poorly investigated. We conducted a multi-omic analysis of immunological parameters in peripheral blood mononuclear cells (PBMCs) of COVID-19 patients with and without cancer. Healthy donors and SARS-CoV-2-negative cancer patients were also included as controls. At the infection peak, cytokine multiplex analysis of blood samples, cytometry by time of flight (CyTOF) cell population analyses, and Nanostring gene expression using Pancancer array on PBMCs were performed. We found that eight pro-inflammatory factors (IL-6, IL-8, IL-13, IL-1ra, MIP-1a, IP-10) out of 27 analyzed serum cytokines were modulated in COVID-19 patients irrespective of cancer status. Diverse subpopulations of T lymphocytes such as CD8 + T, CD4 + T central memory, Mucosal-associated invariant T (MAIT), natural killer (NK), and γδ T cells were reduced, while B plasmablasts were expanded in COVID-19 cancer patients. Our findings illustrate a repertoire of aberrant alterations of gene expression in circulating immune cells of COVID-19 cancer patients. A 19-gene expression signature of PBMCs is able to discriminate COVID-19 patients with and without solid cancers. Gene set enrichment analysis highlights an increased gene expression linked to Interferon α, γ, α/β response and signaling which paired with aberrant cell cycle regulation in cancer patients. Ten out of the 19 genes, validated in a real-world consecutive cohort, were specific of COVID-19 cancer patients independently from different cancer types and stages of the diseases, and useful to stratify patients in a COVID-19 disease severity-manner. We also unveil a transcriptional network involving gene regulators of both inflammation response and proliferation in PBMCs of COVID-19 cancer patients., (© 2021. The Author(s).)

Background: We present immunogenicity data 6 months after the first dose of BNT162b2 in correlation with age, gender, BMI, comorbidities and previous SARS-CoV-2 infection., Methods: An immunogenicity evaluation was carried out among health care workers (HCW) vaccinated at the Istituti Fisioterapici Ospitalieri (IFO). All HCW were asked to be vaccine by the national vaccine campaign at the beginning of 2021. Serum samples were collected on day 1 just prior to the first dose of the vaccine and on day 21 just prior to the second vaccination dose. Thereafter sera samples were collected 28, 49, 84 and 168 days after the first dose of BNT162b2. Quantitative measurement of IgG antibodies against S1/S2 antigens of SARS-CoV-2 was performed with a commercial chemiluminescent immunoassay., Results: Two hundred seventy-four HWCs were analyzed, 175 women (63.9%) and 99 men (36.1%). The maximum antibody geometric mean concentration (AbGMC) was reached at T2 (299.89 AU/mL; 95% CI: 263.53-339.52) with a significant increase compared to baseline ( p < 0.0001). Thereafter, a progressive decrease was observed. At T5, a median decrease of 59.6% in COVID-19 negative, and of 67.8% in COVID-19 positive individuals were identified with respect to the highest antibody response. At T1, age and previous COVID-19 were associated with differences in antibody response, while at T2 and T3 differences in immune response were associated with age, gender and previous COVID-19. At T4 and T5, only COVID-19 positive participants demonstrated a greater antibody response, whereas no other variables seemed to influence antibody levels., Conclusions: Overall our study clearly shows antibody persistence at 6 months, albeit with a certain decline. Thus, the use of this vaccine in addressing the COVID-19 pandemic is supported by our results that in turn open debate about the need for further boosts.

The term "biobanking" is often misapplied to any collection of human biological materials (biospecimens) regardless of requirements related to ethical and legal issues or the standardization of different processes involved in tissue collection. A proper definition of biobanks is large collections of biospecimens linked to relevant personal and health information (health records, family history, lifestyle, genetic information) that are held predominantly for use in health and medical research. In addition, the International Organization for Standardization, in illustrating the requirements for biobanking (ISO 20387:2018), stresses the concept of biobanks being legal entities driving the process of acquisition and storage together with some or all of the activities related to collection, preparation, preservation, testing, analysing and distributing defined biological material as well as related information and data. In this review article, we aim to discuss the basic principles of biobanking, spanning from definitions to classification systems, standardization processes and documents, sustainability and ethical and legal requirements. We also deal with emerging specimens that are currently being generated and shaping the so-called next-generation biobanking, and we provide pragmatic examples of cancer-associated biobanking by discussing the process behind the construction of a biobank and the infrastructures supporting the implementation of biobanking in scientific research., (© 2021. The Author(s).)

Background: The first goal of the study was to analyse the antibody titre 21 days after the first dose of the BNT162b2 vaccine in a group of 252 healthcare workers (HCW). The second goal was to analyse how the antibody titre changes in correlation with age, gender and body mass index (BMI)., Methods: Participants had a nasopharyngeal swab for SARS-CoV-2 and were assessed for the presence of SARS-CoV-2 antibodies at baseline and 21 days after the BNT162b2 priming dose., Results: First dose of BNT162b2 activated immune responses in 98% of the participants. Five HWC had no increase in antibody titre 21 days after the first dose. Antibody titre was greater in young (<38 years) vs. older participants (<38 vs. 47-56 p = 0.002; <38 vs. >56 p = 0.001). Higher antibody levels were detected in underweight vs. pre-obesity group ( p = 0.026) and in normal-weight vs. pre-obesity group ( p = 0.007). This association was confirmed after adjusting for age ( p = 0.0001) and gender ( p = 0.00001)., Conclusions: Our study demonstrates that a single dose of BNT162b2 activates the immune response, and being young and normal-weight correlate positively with this response. Larger specifically designed clinical trials are needed to validate these results.

Background: Literature data suggests that age, gender and body mass index (BMI) could be associated with difference in immune responses to vaccines. The first goal of the study was to analyze the antibody titre seven days after the second dose of BNT162b2 vaccine in a group of 248 healthcare workers (HCWs). The second goal was to analyze how antibody titre changes in correlation with age, gender, BMI and hypertension., Methods: An immunogenicity evaluation was carried out among HCWs vaccinated at the Istituti Fisioterapici Ospitalieri (IFO), Rome, Italy. All HCWs were asked to be vaccinated by the Italian national vaccine campaign at the beginning of 2021. 260 vaccinated HCWs were enrolled in the study. All eligible participants were assigned to receive the priming dose in two weeks' time and the booster dose exactly 21 days thereafter. Blood and nasopharyngeal swabs were collected at baseline and 7 days after second dose of vaccine. Quantitative measurements of IgG antibodies against S1/S2 antigens of SARS-CoV-2 were performed with a commercial chemiluminescent immunoassay. Presence of SARS-Cov-2 in nasopharyngeal swab was determined by commercial RT-PCR testing., Findings: 248 HWCs were analyzed, 158 women (63.7%) and 90 men (36.3%). After the second dose of BNT162b2 vaccine, 99.5% of participants developed a humoral immune response. The geometric mean concentration of antibodies among the vaccinated subjects after booster dose (285.9 AU/mL 95% CI: 249.5-327.7) was higher than that of human convalescent sera (39.4 AU/mL, 95% CI: 33.1-46.9), with p <0.0001. Multivariate linear regression analysis of AU/mL by age, gender and BMI multivariate was performed by the inclusion of covariates. This analysis demonstrated that age ( p <0.0001) and gender ( p  = 0.038) are statistically associated with differences in antibody response after vaccination, whereas BMI and hypertension have no statistically significant association ( p  = 0.078 and p  = 0.52 respectively)., Interpretation: 99.5% of HCW developed a humoral immune response and female and young participants seem to have an increased capacity to mount humoral immune responses. BMI and hypertension seem not associated with difference in immune response to the vaccine., Funding: None., Competing Interests: All authors declare no conflict of interest to disclose., (© 2021 The Author(s).)

Background: Safety and immunogenicity of BNT162b2 mRNA vaccine are unknown in hematological patients; both were evaluated prospectively in 42 patients with multiple myeloma (MM) and 50 with myeloproliferative malignancies (MPM) (20 chronic myeloid leukemias and 30 myeloproliferative neoplasms), all of them on active anti-cancer treatment, in comparison with 36 elderly controls not suffering from cancer. Subjects serologically and/or molecularly (by nasal/throat swab) positives at basal for SARS-CoV-2 were excluded. Primary endpoint was to compare titers of neutralizing anti-SARS-CoV-2 IgG and seroprotection rates among the cohorts at 3 and 5 weeks from first dose., Methods: Titration was done using LIAISON® SARS-CoV-2 S1/S2 IgG test, a quantitative chemiluminescent immunoassay approved by FDA on the basis of robust evidences of concordance (94.4%) between the test at cutoff of 15 AU/mL and the Plaque Reduction Neutralization Test 90% at 1:40 ratio. Cutoff of 15 AU/mL was assumed to discriminate responders to vaccination with a protective titer. Cohorts were compared using Fisher' exact test and the Mann-Whitney test as appropriated. Geometric mean concentrations (GMCs), geometric mean ratios and response rates after 1st and 2nd dose were compared in each cohort by Wilcoxon and McNemar tests, respectively., Results: At 5 weeks, GMC of IgG in elderly controls was 353.3 AU/mL versus 106.7 in MM (p = 0.003) and 172.9 in MPM patients (p = 0.049). Seroprotection rate at cutoff of 15 AU/mL was 100% in controls compared to 78.6% in MM (p = 0.003) and 88% in MPM patients (p = 0.038). In terms of logarithm of IgG titer, in a generalized multivariate linear model, no gender effect was observed (p = 0.913), while there was a significant trend toward lower titers by increasing age (p < 0.001) and in disease cohorts with respect to controls (MM: p < 0.001 and MPM: p < 0.001). An ongoing treatment without daratumumab was associated with higher likelihood of response in MM patients (p = 0.003). No swabs resulted positive on each time point. No safety concerns were observed., Conclusions: BNT162b2 has demonstrated to be immunogenic at different extent among the cohorts. Response was 88% and robust in MPM patients. MM patients responded significantly less, particularly those on anti-CD38-based treatment. These latter patients should be advised to maintain masks and social distancing regardless of vaccination status, and their cohabiting family members need to be vaccinated in order to reduce the risk of contagion from the family. Additional boosters and titer monitoring could be considered. Trial registration Study was formally approved by the IRCCS Central Ethical Committee of Regione Lazio in January 2021 (Prot. N-1463/21).

Purpose: Ultrasound is the recommended modality to assess axillary lymph node involvement in breast cancer; nevertheless, 18 F-fluorodeoxyglucose ( 18 F-FDG) integrated positron emission tomography/computed tomography (PET/CT) diagnostic efficiency, to identify suspicious lesions, is also considered. We aim to report discrepancies in ultrasound and 18 F-FDG PET/CT results., Methods: This single-centered retrospective analysis selected consecutive patients with invasive ductal biopsy-proven breast cancer, for whom divergent 18 F-FDG PET/CT and axillary ultrasound imaging (and/or core needle biopsy if available) had been performed, and described clinical, histological, imaging, and surgery data., Results: This retrospective study included 560 patients and identified discordant results between 18 F-FDG PET/CT and ultrasound (suspicious 18 F-FDG PET/CT and normal ultrasound imaging and/or core needle biopsy) in 20 (4%) patients. Axillary lymph node involvement was confirmed in 17 (85%) out of these 20 patients. Further, the lymph nodes were smaller than one centimeter in 12 (60%) patients, macrometastasic involvement (involvement >2 mm) was detected in 13 (65%) patients, and more than 3 macrometastases were detected in 6 (30%) patients. All patients had an aggressive breast cancer. The sentinel node biopsy performed in 9 (45%) patients allowed to reveal lymph node involvement, even in cases of macrometastatic involvement., Conclusion: Discordant results were issued from normal ultrasound imaging and/or core needle biopsy, and suspicious 18 F-FDG PET/CT revealed that 18 F-FDG PET/CT may overcome axillary ultrasound limits in the specific case of aggressive breast cancers, especially for axillary lymph nodes smaller than 1 centimeter. Sentinel node biopsy remains a valuable aid, even in patients with macrometastatic involvement., (Copyright © 2021. Published by Elsevier Ltd.)

Acid ceramidase (AC) is a cysteine hydrolase that plays a crucial role in the metabolism of lysosomal ceramides, important members of the sphingolipid family, a diversified class of bioactive molecules that mediate many biological processes ranging from cell structural integrity, signaling, and cell proliferation to cell death. In the effort to expand the structural diversity of the existing collection of AC inhibitors, a novel class of substituted oxazol-2-one-3-carboxamides were designed and synthesized. Herein, we present the chemical optimization of our initial hits, 2-oxo-4-phenyl- N -(4-phenylbutyl)oxazole-3-carboxamide 8a and 2-oxo-5-phenyl- N -(4-phenylbutyl)oxazole-3-carboxamide 12a , which resulted in the identification of 5-[4-fluoro-2-(1-methyl-4-piperidyl)phenyl]-2-oxo- N -pentyl-oxazole-3-carboxamide 32b as a potent AC inhibitor with optimal physicochemical and metabolic properties, showing target engagement in human neuroblastoma SH-SY5Y cells and a desirable pharmacokinetic profile in mice, following intravenous and oral administration. 32b enriches the arsenal of promising lead compounds that may therefore act as useful pharmacological tools for investigating the potential therapeutic effects of AC inhibition in relevant sphingolipid-mediated disorders.

Muscle weakness and fatigue represent frequent disabling symptoms for Multiple Sclerosis (MS) patients. We evaluated the effects of an intensive task-oriented circuit training (TOCT) on perceived fatigue, muscle strength and changes in motor performance fatigability in mildly impaired MS patients. Fifteen MS patients performed different functional scales, self-reported questionnaires and instrumental evaluations before (T0) and after (T1) TOCT. Strength and performance fatigability were analyzed during isometric knee extension and ankle dorsiflexion through an isokinetic dinamometer, recording surface EMG signals of Vastus Medialis and Tibialis Anterior. The Dinamic Gait Index, Multiple Sclerosis Impact Scale-29, Modified Fatigue Impact Scale and Multiple Sclerosis Walking Scale-12 significantly improved after training. An increase of exerted force during isometric knee extension was observed, whereas no significant changes were revealed on mechanical and electrical fatigue. Moreover, the improvement in perceived disability after treatment was related to strength increase in knee mechanical force output. The TOCT positively modifies perceived fatigue, perceived ambulatory function and knee force output in mildly impaired MS subjects, suggesting a virtuous circle between strength levels, recovery of functional skills and improved quality of life., Competing Interests: We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.