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Abstract Objective The dentato‐thalamo‐cortical tract (DTT) is the main cerebellar efferent pathway. Degeneration of the DTT is a core feature of Friedreich ataxia (FRDA). However, it remains unclear whether DTT disruption is spatially specific, with some segments being more impacted than others. This study aimed to investigate microstructural integrity along the DTT in FRDA using a profilometry diffusion MRI (dMRI) approach. Methods MRI data from 45 individuals with FRDA (mean age: 33.2 ± 13.2, Male/Female: 26/19) and 37 healthy controls (mean age: 36.5 ± 12.7, Male/Female:18/19) were included in this cross‐sectional multicenter study. A profilometry analysis was performed on dMRI data by first using tractography to define the DTT as the white matter pathway connecting the dentate nucleus to the contralateral motor cortex. The tract was then divided into 100 segments, and dMRI metrics of microstructural integrity (fractional anisotropy, mean diffusivity and radial diffusivity) at each segment were compared between groups. The process was replicated on the arcuate fasciculus for comparison. Results Across all diffusion metrics, the region of the DTT connecting the dentate nucleus and thalamus was more impacted in FRDA than downstream cerebral sections from the thalamus to the cortex. The arcuate fasciculus was minimally impacted. Interpretation Our study further expands the current knowledge about brain involvement in FRDA, showing that microstructural abnormalities within the DTT are weighted to early segments of the tract (i.e., the superior cerebellar peduncle). These findings are consistent with the hypothesis of DTT undergoing anterograde degeneration arising from the dentate nuclei and progressing to the primary motor cortex.

The present study was designed to assess the influence of fishmeal replacement with increasing percentages of fresh seafood discards (0, 25, 50 and 75%) in diets for Penaeus japonicus on growth performance, physical characteristics and the chemical and fatty acid composition of shrimp flesh. Each diet was administered for 108 days, and the trial was assayed in triplicate. The final body weight and the specific growth rate were significantly higher (p < 0.05) in shrimps fed with 75% fishmeal replacement as compared to 25%, while the abdomen weight and the total length were the highest (p < 0.01). Moreover, 75% replacement showed a significantly (p < 0.05) lower value of hardness and a greater crude protein and lipid content as compared to the 0% replacement. The shrimps fed with high levels of seafood discards (50 and 75%) showed a lower saturated fatty acid concentration and, in turn, a greater amount of polyunsaturated fatty acids in shrimp meat significantly (p < 0.05) affected the lower atherogenic and thrombogenic indices. In conclusion, replacing 75% of fishmeal with seafood discards provided satisfactory results. An economic analysis based on ESG indicators and PESTLE methodology is provided in order to show the socio-economic and governance impacts affecting the replacement of shrimps’ diet with fish discard.

Abstract Early in the COVID-19 pandemic, it emerged that the risk of severe outcomes was greater in patients with co-morbidities, including cancer. The huge effort undertaken to fight the pandemic, affects the management of cancer care, influencing their outcome. Despite the high fatality rate of COVID-19 disease in cancer patients, rare cases of temporary or prolonged clinical remission from cancers after SARS-CoV-2 infection have been reported. We have reviewed sixteen case reports of COVID-19 disease with spontaneous cancer reduction of progression. Fourteen cases of remission following viral infections and two after anti-SARS-CoV-2 vaccination. The immune response to COVID-19, may be implicated in both tumor regression, and progression. Specifically, we discuss potential mechanisms which include oncolytic and priming hypotheses, that may have contributed to the cancer regression in these cases and could be useful for future options in cancer treatment.

Abstract Sharp dose gradients and high biological effectiveness make ions such as 12C an ideal tool to treat deep-seated tumors, however, at the same time, sensitive to errors in the range prediction. Tumor safety margins mitigate these uncertainties, but during the irradiation they lead to unavoidable damage to the surrounding healthy tissue. To fully exploit the Bragg peak benefits, a large effort is put into establishing precise range verification methods. Despite positron emission tomography being widely in use for this purpose in 12C therapy, the low count rates, biological washout, and broad activity distribution still limit its precision. Instead, radioactive beams used directly for treatment would yield an improved signal and a closer match with the dose fall-off, potentially enabling precise in vivo beam range monitoring. We have performed a treatment planning study to estimate the possible impact of the reduced range uncertainties, enabled by radioactive 11C ions treatments, on sparing critical organs in tumor proximity. Compared to 12C treatments, (i) annihilation maps for 11C ions can reflect sub- millimeter shifts in dose distributions in the patient, (ii) outcomes of treatment planning with 11C significantly improve and (iii) less severe toxicities for serial and parallel critical organs can be expected.

Atherina boyeri is the primary source of fishing profit in Lake Trasimeno and a common host for Eustrongylides spp. larvae. The presence of Eustrongylides in fish is a public health concern, and effective risk management procedures are necessary to guarantee that infected products do not reach the market. Currently, in the European Union, there is no official sampling plan for fresh fish that defines sample size, inspection methods, and criteria for accepting or rejecting the product. An approach to Eustrongylides risk management is proposed in this study. A total of 270 batches of Atherina boyeri, each consisting of 29 specimens, were collected and examined visually in 3 years (2020-2023). The prevalence (P) of the parasite was 20% in 2020, and in the first months of 2021, it grew up to ⁓40%, then dropped to 12.50% in December 2021 and settled at 16% in February 2022. In January and February 2023, the P fell below 1%. The mean abundance was calculated and used to establish a threshold value to determine fish marketability. In 2020 and 2021, several batches were judged not marketable, and in some batches, a freezing treatment was implemented to assure the inactivation of the parasite. In the last months of 2022 and in January and February of 2023, the presence of parasites in captured fish was negligible, and this allowed the marketability of fish as fresh. The proposed sampling plan was effective in preventing the commercialization of potentially hazardous products.

Fish are good bio-indicators of the health status of the aquatic environment and can be used as biomarkers to assess the aquatic behavior of environmental pollutants, the exposure of aquatic organisms, and the health risk for consumers. Goldfish are a significant bioindicator in the Lake Trasimeno aquatic system (Umbria, Italy). This study aimed to characterize the health status and the chemical and biotic contamination of Lake Trasimeno to define its anthropogenic and natural pressures and the risk associated with consuming its fishery products. 114 determinations were performed on Carassius auratus samples from 2018 to 2020, and the occurrence of brominated flame retardants, non-dioxin-like polychlorinated biphenyls, heavy metals, and microplastics was analytically investigated. Dietary exposure assessment, risk characterization, and benefit-risk evaluation were performed for schoolchildren from 3 to 10 years old. Flame-retardants registered high levels of non-detects (99% for polybrominated diphenyl ether and 76% for hexabromocyclododecanes), while polychlorinated biphenyls were found in all samples with a maximum level of 56.3 ng/g. Traces of at least one heavy metal were found in all samples, though always below the regulatory limit. Microplastics were found with a 75% frequency of fish ingesting at least one particle. Dietary exposure and risk characterization reveal negligible contributions to the reference values of all contaminants, except for mercury, which reached up to 25% of admissible daily intake. The benefit-risk assessment highlighted that the benefits of freshwater fish intake outweigh the associated risks. The examination of goldfish as indicator fish reveals the quality of Lake Trasimeno's aquatic environment and the safety of its products.

BackgroundImmune checkpoint inhibitors (ICIs) have significantly changed the oncology clinic in recent years, improving survival expectations in cancer patients. ICI therapy have a broad spectrum of side effects from endocrinopathies to cardiovascular diseases. In this study, pro-inflammatory and pro-fibrotic effects of short-term ICIs therapy in preclinical models were analyzed.MethodsFirstly, in a human in vitro model, human cardiomyocytes co-cultured with hPBMC were exposed to ICIs (with CTLA-4 or PD-1 blocking agents, at 200 nM) for 72 h. After treatment, production of DAMPs and 12 cytokines were analyzed in the supernatant through colorimetric and enzymatic assays. C57/Bl6 mice were treated with CTLA-4 or PD-1 blocking agents (15 mg/kg) for 10 days. Before (T0), after three days (T3) and after treatments (T10), ejection fraction, fractional shortening, radial and longitudinal strain were calculated by using bidimensional echocardiography (Vevo 2100, Fujfilm). Fibrosis, necrosis, hypertrophy and vascular NF-kB expression were analyzed through Immunohistochemistry. Myocardial expression of DAMPs (S100- Calgranulin, Fibronectin and Galectine-3), MyD88, NLRP3 and twelve cytokines have been analyzed. Systemic levels of SDF-1, IL-1β, and IL-6 were analyzed before, during and after ICIs therapy.ResultsRadial and longitudinal strain were decreased after 10 days of ICIs therapy. Histological analysis of NF-kB expression shows that short-term anti-CTLA-4 or anti-PD-1 treatment increased vascular and myocardial inflammation. No myocardial hypertrophy was seen with the exception of the pembrolizumab group. Myocardial fibrosis and expression of galectin-3, pro-collagen 1-α and MMP-9 were increased after treatment with all ICIs. Both anti-CTLA-4 or anti-PD-1 treatments increased the expression of DAMPs, NLRP3 inflammasome and MyD88 and induced both in vitro and in vivo the secretion of IL-1β, TNF-α and IL-6. Systemic levels of SDF-1, IL-1β and IL-6 were increased during and after treatment with ICIs.ConclusionsShort therapy with PD-1 and CTLA-4 blocking agents increases vascular expression of NF-kB, systemic SDF-1, IL-1β, IL-6 levels and myocardial NLRP3, MyD88 and DAMPs expression in preclinical models. A pro-inflammatory cytokine storm was induced in myocardial tissues and in cultured cardiac cells after ICIs therapy. The overall picture of the study suggests new putative biomarkers of ICIs-mediated systemic and myocardial damages potentially useful in clinical cardioncology.

Anthracyclines are essential adjuvant therapies for a variety of cancers, particularly breast, gastric and esophageal cancers. Whilst prolonging cancer-related survival, these agents can induce drug-related cardiotoxicity. Spirulina, Reishi (Ganoderma lucidum) and Moringa are three nutraceuticals with anti-inflammatory effects that are currently used in cancer patients as complementary and alternative medicines to improve quality of life and fatigue. We hypothesize that the nutraceutical combination of Spirulina, Reishi and Moringa (Singo) could reduce inflammation and cardiotoxicity induced by anthracyclines. Female C57Bl/6 mice were untreated (Sham, n = 6) or treated for 7 days with short-term doxorubicin (DOXO, n = 6) or Singo (Singo, n = 6), or pre-treated with Singo for 3 days and associated with DOXO for remaining 7 days (DOXO–Singo, n = 6). The ejection fraction and radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100, Fujifilm, Tokyo, Japan). The myocardial expressions of NLRP3, DAMPs (galectin-3 and calgranulin S100) and 13 cytokines were quantified through selective mouse ELISA methods. Myocardial fibrosis, necrosis and hypertrophy were analyzed through immunohistochemistry (IHC). Human cardiomyocytes were exposed to DOXO (200 nM) alone or in combination with Singo (at 10, 25 and 50 µg/mL) for 24 and 48 h. Cell viability and inflammation studies were also performed. In preclinical models, Singo significantly improved ejection fraction and fractional shortening. Reduced expressions of myocardial NLRP3 and NF-kB levels in cardiac tissues were seen in DOXO–Singo mice vs. DOXO (p < 0.05). The myocardial levels of calgranulin S100 and galectin-3 were strongly reduced in DOXO–Singo mice vs. DOXO (p < 0.05). Immunohistochemistry analysis indicates that Singo reduces fibrosis and hypertrophy in the myocardial tissues of mice during exposure to DOXO. In conclusion, in the preclinical model of DOXO-induced cardiotoxicity, Singo is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis.

The increasing world market demand for seafood requires an expansion of product categories available to consumers. Inland fish are usually considered having unmarked taste and are less appreciated by consumers; thus, they have low commercial value. Therefore, the marketing of the lake’s fresh and processed fish is limited to the local market and consumers are currently uninformed and mistrustful about these species. In this study, six different fish species were caught in the Fondi lake (Lazio, central Italy): Anguilla anguilla, Tinca tinca, Carassius gibelio, Cyprinus carpio, Micropterus salmoides, Chelon ramada. All the samples were subjected to nutritional and DNA barcoding analysis. Moisture, protein, fat, carbohydrates, ash, and sodium content were measured. As regards the fatty acids profile, the most abundant were MUFAs with the highest value in Anguilla anguilla (45.97%). Oleic acid (C18: 1 n9 cis) was particularly high in Cyprinus carpio (55.46%). The fraction of polyunsaturated fatty acids (PUFA) revealed a higher DHA content (C22: 6 n3) in Anguilla anguilla than the other species (>12 %) while Chelon ramada presented both higher EPA content (C 20: 5 n3) and total fraction of omega 3 PUFAs. Concerning molecular analysis, a 655 bp fragment of cytochrome C oxidase subunit I (COI) gene was successfully used for the identification at the species level using both BOLD and BLAST public databases. The present study gives the basis for improving the knowledge and promoting inland fish’ market and traceability along the supply chain.

Tumor Associated Antigens (TAAs) may suffer from an immunological tolerance due to expression on normal cells. In order to potentiate their immunogenicity, heteroclitic peptides (htcPep) were designed according to prediction algorithms. In particular, specific modifications were introduced in peptide residues facing to TCR. Moreover, a MHC-optimized scaffold was designed for improved antigen presentation to TCR by H-2Db allele. The efficacy of such htcPep was assessed in C57BL/6 mice injected with syngeneic melanoma B16F10 or lung TC1 tumor cell lines, in combination with metronomic chemotherapy and immune checkpoint inhibitors. The immunogenicity of htcPep was significantly stronger than the corresponding wt peptide and the modification involving both MHC and TCR binding residues scored the strongest. In particular, the H-2Db-specific scaffold significantly potentiated the peptides’ immunogenicity and control of tumor growth was comparable to wt peptide in a therapeutic setting. Overall, we demonstrated that modified TAAs show higher immunogenicity compared to wt peptide. In particular, the MHC-optimized scaffold can present different antigen sequences to TCR, retaining the conformational characteristics of the corresponding wt. Cross-reacting CD8+ T cells are elicited and efficiently kill tumor cells presenting the wild-type antigen. This novel approach can be of high clinical relevance in cancer vaccine development.

Abstract Background Platelet-rich-plasma (PRP) is largely used, thanks to its properties, as wound therapy after surgical resection. Several studies and clinical findings have demonstrated that the PRP can accelerate the regeneration and the repair of tissues through the action of the platelet-derived growth factors. Material and methods Our study aimed to investigate the effects of PRP-gel on the rate of tumor relapse by using a mouse model of Human Fibrosarcoma (HF). The radical resection of tumors of mice was conducted under fluorescence-guidance (FGR) by using MacroFluo microscope, after a primary tumor removal with bright-light surgery (BLS). Results It was found that the lesion recurrence and the tumor growth were reduced in mice treated with PRP observed in each group of treatment (50%) after 30 days from tumor excision, respect to controls (without statistical significance; p = 0.12). The histopathological and immune-histochemical analysis did not report differences in cellular morphology between the tumors of control and PRP-treated mice. Conclusion Our data suggest that PRP-gel, used as an adjuvant treatment for the stimulation of tissue repair and speed up recovery, can impair tumor growth and slow the tumor.

Proper regulation of neurogenesis, the process by which new neurons are generated from neural stem and progenitor cells (NS/PCs), is essential for embryonic brain development and adult brain function. The transcription regulator Patz1 is ubiquitously expressed in early mouse embryos and has a key role in embryonic stem cell maintenance. At later stages, the detection of Patz1 expression mainly in the developing brain suggests a specific involvement of Patz1 in neurogenesis. To address this point, we first got insights in Patz1 expression profile in different brain territories at both embryonic and postnatal stages, evidencing a general decreasing trend with respect to time. Then, we performed in vivo and ex vivo analysis of Patz1-knockout mice, focusing on the ventricular and subventricular zone, where we confirmed Patz1 enrichment through the analysis of public RNA-seq datasets. Both embryos and adults showed a significant reduction in the number of Patz1-null NS/PCs, as well as of their self-renewal capability, compared to controls. Consistently, molecular analysis revealed the downregulation of stemness markers in NS/PCs derived from Patz1-null mice. Overall, these data demonstrate the requirement of Patz1 for NS/PC maintenance and proliferation, suggesting new roles for this key transcription factor specifically in brain development and plasticity, with possible implications for neurodegenerative disorders and glial brain tumors.

SARS-CoV-2 infection is a new threat to global public health in the 21st century (2020), which has now rapidly spread around the globe causing severe pneumonia often linked to Acute Respiratory Distress Syndrome (ARDS) and hyperinflammatory syndrome. SARS-CoV-2 is highly contagious through saliva droplets. The structural analysis suggests that the virus enters human cells through the ligation of the spike protein to angiotensin-converting enzyme 2 (ACE2). The progression of Covid-19 has been divided into three main stages: stage I—viral response, stage II—pulmonary phase, and stage III—hyperinflammation phase. Once the patients enter stage III, it will likely need ventilation and it becomes difficult to manage. Thus, it will be of paramount importance to find therapies to prevent or slow down the progression of the disease toward stage III. The key event leading to hyperinflammation seems to be the activation of Th-17 immunity response and Cytokine storm. B2-adrenergic receptors (B2ARs) are expressed on airways and on all the immune cells such as macrophages, dendritic cells, B and T lymphocytes. Blocking (B2AR) has been proven, also in clinical settings, to reduce Th-17 response and negatively modulate inflammatory cytokines including IL-6 while increasing IFNγ. Non-selective beta-blockers are currently used to treat several diseases and have been proven to reduce stress-induced inflammation and reduce anxiety. For these reasons, we speculate that targeting B2AR in the early phase of Covid-19 might be beneficial to prevent hyperinflammation.

The spread of the novel human respiratory coronavirus (SARS-CoV-2) is a global public health emergency. There is no known successful treatment as of this time, and there is a need for medical options to mitigate this current epidemic. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and is primarily trophic for the lower and upper respiratory tract. A number of current studies on COVID-19 have demonstrated the substantial increase in pro-inflammatory factors in the lungs during infection. The virus is also documented in the central nervous system and, particularly in the brainstem, which plays a key role in respiratory and cardiovascular function. Currently, there are few antiviral approaches, and several alternative drugs are under investigation. Two of these are Idelalisib and Ebastine, already proposed as preventive strategies in airways and allergic diseases. The interesting and evolving potential of phosphoinositide 3-kinase δ (PI3Kδ) inhibitors, together with Ebastine, lies in their ability to suppress the release of pro-inflammatory cytokines, such as IL-1β, IL-8, IL-6, and TNF-α, by T cells. This may represent an optional therapeutic choice for COVID-19 to reduce inflammatory reactions and mortality, enabling patients to recover faster. This concise communication aims to provide new potential therapeutic targets capable of mitigating and alleviating SARS-CoV-2 pandemic infection.

Radiation therapy (RT) of thoracic cancers may cause severe radiation dermatitis (RD), which impacts on the quality of a patient's life. Aim of this study was to analyze the incidence of acute RD and develop normal tissue complication probability (NTCP) models for severe RD in thoracic cancer patients treated with Intensity-Modulated RT (IMRT) or Passive Scattering Proton Therapy (PSPT). We analyzed 166 Non-Small-Cell Lung Cancer (NSCLC) patients prospectively treated at a single institution with IMRT (103 patients) or PSPT (63 patients). All patients were treated to a prescribed dose of 60 to 74 Gy in conventional daily fractionation with concurrent chemotherapy. RD was scored according to CTCAE v3 scoring system. For each patient, the epidermis structure (skin) was automatically defined by an in house developed segmentation algorithm. The absolute dose-surface histogram (DSH) of the skin were extracted and normalized using the Body Surface Area (BSA) index as scaling factor. Patient and treatment-related characteristics were analyzed. The Lyman-Kutcher-Burman (LKB) NTCP model recast for DSH and the multivariable logistic model were adopted. Models were internally validated by Leave-One-Out method. Model performance was evaluated by the area under the receiver operator characteristic curve, and calibration plot parameters. Fifteen of 166 (9%) patients developed severe dermatitis (grade 3). RT technique did not impact RD incidence. Total gross tumor volume (GTV) size was the only non dosimetric variable significantly correlated with severe RD (p = 0.027). Multivariable logistic modeling resulted in a single variable model including S20Gy, the relative skin surface receiving more than 20 Gy (OR = 31.4). The cut off for S20Gy was 1.1% of the BSA. LKB model parameters were TD50 = 9.5 Gy, m = 0.24, n = 0.62. Both NTCP models showed comparably high prediction and calibration performances. Despite skin toxicity has long been considered a potential limiting factor in the clinical use of PSPT, no significant differences in RD incidence was found between RT modalities. Once externally validated, the availability of NTCP models for prediction of severe RD may advance treatment planning optimization.

Abstract Background Technological advances in Hodgkin lymphoma (HL) radiation therapy (RT) by high conformal treatments potentially increase control over organs-at-risk (OARs) dose distribution. However, plan optimization remains a time-consuming task with great operator dependent variability. Purpose of the present study was to devise a fully automated pipeline based on the Pinnacle3 Auto-Planning (AP) algorithm for treating female supradiaphragmatic HL (SHL) patients. Methods CT-scans of 10 female patients with SHL were considered. A “butterfly” (BF) volumetric modulated arc therapy was optimized using SmartArc module integrated in Pinnacle3 v. 9.10 using Collapsed Cone Convolution Superposition algorithm (30 Gy in 20 fractions). Human-driven (Manual-BF) and AP-BF optimization plans were generated. For AP, an optimization objective list of Planning Target Volume (PTV)/OAR clinical goals was first implemented, starting from a subset of 5 patients used for algorithm training. This list was then tested on the remaining 5 patients (validation set). In addition to the BF technique, the AP engine was applied to a 2 coplanar disjointed arc (AP-ARC) technique using the same objective list. For plan evaluation, dose-volume-histograms of PTVs and OARs were extracted; homogeneity and conformity indices (HI and CI), OARs dose-volume metrics and odds for different toxicity endpoints were computed. Non-parametric Friedman and Dunn tests were used to identify significant differences between groups. Results A single AP objective list for SHL was obtained. Compared to the manual plan, both AP-plans offer comparable CIs while AP-ARC also achieved comparable HIs. All plans fulfilled the clinical dose criteria set for OARs: both AP solutions performed at least as good as Manual-BF plan. In particular, AP-ARC outperformed AP-BF in terms of heart sparing involving a lower risk of coronary events and radiation-induced lung fibrosis. Hands-on planning time decreased by a factor of 10 using AP on average. Conclusions Despite the high interpatient PTV (size and position) variability, it was possible to set a standard SHL AP optimization list with a high level of generalizability. Using the implemented list, the AP module was able to limit OAR doses, producing clinically acceptable plans with stable quality without additional user input. Overall, the AP engine associated to the arc technique represents the best option for SHL.

Abstract The risk of radiation-induced toxicity in patients treated for head and neck (HN) cancer with radiation therapy (RT) is traditionally estimated by condensing the 3D dose distribution into a monodimensional cumulative dose-volume histogram which disregards information on dose localization. We hypothesized that a voxel-based approach would identify correlations between radiation-induced morbidity and local dose release, thus providing a new insight into spatial signature of radiation sensitivity in composite regions like the HN district. This methodology was applied to a cohort of HN cancer patients treated with RT at risk of radiation-induced acute dysphagia (RIAD). We implemented an inter-patient elastic image registration framework that proved robust enough to match even the most elusive HN structures and to provide accurate dose warping. A voxel-based statistical analysis was then performed to test regional dosimetric differences between patients with and without RIAD. We identified a significantly higher dose delivered to RIAD patients in two voxel clusters in correspondence of the cricopharyngeus muscle and cervical esophagus. Our study goes beyond the well-established organ-based philosophy exploring the relationship between radiation-induced morbidity and local dose differences in the HN region. This approach is generally applicable to different HN toxicity endpoints and is not specific to RIAD.

In radiation oncology, the need for a modern Normal Tissue Complication Probability (NTCP) philosophy to include voxel-based evidence on organ radio-sensitivity (RS) has been acknowledged. Here a new formalism (Probabilistic Atlas for Complication Estimation, PACE) to predict radiation-induced morbidity (RIM) is presented. The adopted strategy basically consists in keeping the structure of a classical, phenomenological NTCP model, such as the Lyman-Kutcher-Burman (LKB), and replacing the dose distribution with a collection of RIM odds, including also significant non-dosimetric covariates, as input of the model framework. The theory was first demonstrated in silico on synthetic dose maps, classified according to synthetic outcomes. PACE was then applied to a clinical dataset of thoracic cancer patients classified for lung fibrosis. LKB models were trained for comparison. Overall, the obtained learning curves showed that the PACE model outperformed the LKB and predicted synthetic outcomes with an accuracy >0.8. On the real patients, PACE performance, evaluated by both discrimination and calibration, was significantly higher than LKB. This trend was confirmed by cross-validation. Furthermore, the capability to infer the spatial pattern of underlying RS map for the analyzed RIM was successfully demonstrated, thus paving the way to new perspectives of NTCP models as learning tools.

Radiation therapy (RT) is a constantly evolving therapeutic technique; improvements are continuously being introduced for both methodological and practical aspects. Among the features that have undergone a huge evolution in recent decades, dose calculation algorithms are still rapidly changing. This process is propelled by the awareness that the agreement between the delivered and calculated doses is of paramount relevance in RT, since it could largely affect clinical outcomes. The aim of this work is to provide an overall picture of the main dose calculation algorithms currently used in RT, summarizing their underlying physical models and mathematical bases, and highlighting their strengths and weaknesses, referring to the most recent studies on algorithm comparisons. This handy guide is meant to provide a clear and concise overview of the topic, which will prove useful in helping clinical medical physicists to perform their responsibilities more effectively and efficiently, increasing patient benefits and improving the overall quality of the management of radiation treatment.

The synthesis and the biological activity of novel semi-synthetic β-lactam compounds containing an azetidinone moiety joined to the amino-nitrogen of the (+)-6-aminopenicillanic acid (6-APA) as new antibacterial agents is reported. The synthesized compounds were screened for their in vitro antimicrobial activity against a panel of Gram positive and Gram negative pathogens and environmental bacteria. Tested compounds displayed good antimicrobial activity against all tested Gram positive bacteria and for Staphylococcus aureus and Staphylococcus epidermidis antimicrobial activity resulted higher than that of the reference antibiotic. Additionally, in vitro cytotoxic screening was also carried out indicating that the compounds do not cause a cell vitality reduction effective at concentration next to and above those shown to be antimicrobial.

An accurate design of an innovative fiber optic temperature sensor is developed. The sensor is based on a cascade of three microstructured optical fibers (MOFs). In the first one a suitable cascade of long period gratings is designed into the core. A single mode intermediate and a rare-earth activated Fabry-Perot optical cavity are the other two sensor MOF sections. An exhaustive theoretic feasibility investigation is performed employing computer code. The complete set-up for temperature monitoring can be obtained by utilizing only a low cost pump diode laser at 980 nm wavelength and a commercial optical power detector. The simulated sensitivity S = 315.1 μW/°C and the operation range ΔT = 100 °C is good enough for actual applications.

The European Food Safety Authority stated that many traditional marinating and cold smoking methods are not sufficient to kill A. simplex and asked to evaluate alternative treatments for killing viable parasites in fishery. Baccalà is a well-liked traditional product. The aim of study was to evaluate the effectiveness of the salting process on the inactivation of nematodes of the genus Anisakis in naturally infected Baccalà fillets. N. 19 fillets, subjected to a dual salting process (brine and dry salting) were analyzed. Visual inspection and chloropeptic digestion were performed. Larvae viability was evaluated, and parameters such as NaCl (%), moisture (%), WPS and aw were determined. In n. 17 samples parasites were found 123 parasites with a mean intensity of 7.23±4.78 and an mean abundance of 6.47±5.05. Visual examination has revealed 109 parasites. 61.8% of larvae were found in the ventral portions. The results show that salting process with a salt concentration of 18.6%, aw values of 0.7514 and 24.15% WPS in all parts of baccalà fillets, devitalise Anisakidae larvae in a 15-day period.

BackgroundBrain MRI plays an essential role in both diagnosis and follow-up of the JC virus infection of the brain. Recently, MR studies with susceptibility-weighted imaging (SWI) sequences have shown hypointensities in U-fibers adjacent to white matter (WM) lesions of progressive multifocal leukoencephalopathy (PML). This finding has been confirmed with the use of quantitative susceptibility mapping (QSM), allowing to hypothesize a paramagnetic effect in these regions. Here, we report the first longitudinal assessment of QSM and R2* maps in natalizumab-associated PML to evaluate serial changes in susceptibility contrast images and their role in PML diagnosis and follow-up.Case presentationWe report the case of a 42-year-old woman with multiple sclerosis (MS) who eventually developed, after the 28th natalizumab infusion, subacute cognitive decline and received a laboratory-confirmed diagnosis of PML, leading to immediate drug discontinuation. Three months later, she suffered a new clinical exacerbation, with a brain scan revealing significant inflammatory activity compatible with the radiological diagnosis of an Immune Reconstitution Inflammatory Syndrome (IRIS). She was then treated with corticosteroids until the clinico-radiological spectrum became stable, with the final outcome of a severe functional impairment. Quantitative maps obtained in the early symptomatic stage clearly showed increased QSM and R2* values in the juxtacortical WM adjacent to PML lesions, which persisted during the subsequent disease course.Discussion and conclusionHigh QSM and R2* values in U-fibers adjacent to WM lesions were early and seemingly time-independent radiological findings in the presented PML case. This, coupled to the known absence of significant paramagnetic effect of new active MS lesions, could support the use of quantitative MRI as an additional tool in the diagnosis and follow-up of natalizumab-related PML in MS.

Previous studies showed that fish mitochondrial DNA (mtDNA) is set up by a closed circular molecule of 16-17 kilobases (kb), comprising 2 ribosomal RNA genes (rRNA), 22 transfer RNA genes (tRNA), 13 protein-coding genes and 2 non-coding regions. The analysis of single mtDNA genes, such as Cytb, COI, 16S and 12S, or short segment of them, has been widely used against species substitution in both fresh and processed fish products. The analysis of the complete mitochondrial genome of fishery products allows to better study and characterise fish species. The aim of this research was to extract and amplify the complete mtDNA of some fish species of commercial interest belonging to the Sparidae family. The studied species were Dentex dentex, Dentex gibbosus, Dentex nufar, Pagellus acarne and Pagellus erythrinus. The entire mitogenome was obtained by gene amplification using long polymerase chain reactions. The analysis of the complete mitochondrial sequences will allow to gain further insights on these species and to find polymorphic sites that assess the degree of genetic variability of the species belonging to the family Sparidae.

The complete mitochondrial genome of the Angolan dentex (Dentex angolensis, Poll and Maul, 1953) is 16.581 bp in length and contains 13 protein-coding genes, 22 transfer RNA genes, and 2 ribosomal RNA genes. The overall base composition of D. angolesis mtDNA is: 27.4% for A, 28% for C, 16.7% for G, 27.9% for T. Phylogenetic analysis indicated that D. angolensis is most closely related to D. tumifrons. Whole genome sequencing of D. angolensis mitochondrial DNA will contribute to improving knowledge about Sparidae evolution.

We have recently generated knockout mice for the Cbx7 gene, coding for a polycomb group protein that is downregulated in human malignant neoplasias. These mice develop liver and lung adenomas and carcinomas, which confirms a tumour suppressor role for CBX7. The CBX7 ability to downregulate CCNE1 expression likely accounts for the phenotype of the Cbx7-null mice. Unexpectedly, Cbx7-knockout mice had a higher fat tissue mass than wild-type, suggesting a role of CBX7 in adipogenesis. Consistently, we demonstrate that Cbx7-null mouse embryonic fibroblasts go towards adipocyte differentiation more efficiently than their wild-type counterparts, and this effect is Cbx7 dose-dependent. Similar results were obtained when Cbx7-null embryonic stem cells were induced to differentiate into adipocytes. Conversely, mouse embryonic fibroblasts and human adipose-derived stem cells overexpressing CBX7 show an opposite behaviour. These findings support a negative role of CBX7 in the control of adipocyte cell growth and differentiation.

The HMGA1 and HMGA2 genes code for proteins belonging to the High Mobility Group A family. Several genes are negatively or positively regulated by both these proteins, but a number of genes are specifically regulated by only one of them. Indeed, knock-out of the Hmga1 and Hmga2 genes leads to different phenotypes: cardiac hypertrophy and type 2 diabetes in the former case, and a large reduction in body size and amount of fat tissue in the latter case. Therefore, to better elucidate the functions of the Hmga genes, we crossed Hmga1-null mice with mice null for Hmga2. The Hmga1−/−/Hmga2−/− mice showed reduced vitality and a very small size (75% smaller than the wild-type mice); they were even smaller than pygmy Hmga2-null mice. The drastic reduction in E2F1 activity, and consequently in the expression of the E2F-dependent genes involved in cell cycle regulation, likely accounts for some phenotypic features of the Hmga1−/−/Hmga2−/− mice.

The Pink dentex (Dentex gibbosus, Rafinesque 1810) is one of the most commercially important Sparidae species and it is often subjected to fraud. Here, we report the complete mitochondrial genome of D. gibbosus. The mitogenome is 16,771 bp in length and contained 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and 2 non-coding regions. The overall base composition of D. gibbosus mtDNA is: 27.8% for A, 28.60% for C, 16.5% for G, 27.05% for T.

The common pandora (Pagellus erythrinus, Linnaeus 1758), one of the most popular sea bream species in the Mediterranean Sea, has high potential for aquaculture development. In this investigation, we analyzed the complete mitochondrial genome of P. erythrinus. The sequence has 16,828 bp in length and consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and a two non-coding regions (D-loop and L-origin). The overall nucleotide composition is: 27.5% of A, 28.2% of C, 27.5% of T, and 16.8% of G.

Human cases of gastric anisakiasis caused by the zoonotic parasite Anisakis pegreffii are increasing in Italy. The disease is caused by ingestion of larval nematodes in lightly cooked or raw seafood. Because symptoms are vague and serodiagnosis is difficult, the disease is often misdiagnosed and cases are understimated.

A new additive formulation containing hydrogen peroxide, citric acid and trisodium acid is illegally used in fishery products due its whitening and antioxidant features. Aim of this study was to evaluate the possible presence of COPs and their role as markers of illegal treatment in anchovies (Engraulis encrasicolus) stored at different temperatures. Sensory analysis was also performed by the specific QIM test. The quantitative determinations (%) of cholesterol oxides (COPs) showed changing amounts during storage. Not always The COPs measured in the treated samples were significantly higher than control samples. Considering the volatility of hydrogen peroxide and the poor repeatability of COPs analyses, as shown in the present study, it is crucial to intensify the control by the Authorities.

Susceptibility Weighted Imaging (SWI) is a common MRI technique that exploits the magnetic susceptibility differences between the tissues to provide valuable image contrasts, both in research and clinical contexts. However, despite its increased clinical use, SWI is not intrinsically suitable for quantitation purposes. Conversely, quantitative Magnetic Resonance Imaging (qMRI) provides a way to disentangle the sources of common MR image contrasts (e.g. proton density, T1, etc.) and to measure physical parameters intrinsically related to tissue microstructure. Unfortunately, the poor signal-to-noise ratio and resolution, coupled with the long imaging time of most qMRI strategies, have hindered the integration of quantitative imaging into clinical protocols. Here we present the RElaxometry and SUsceptibility Mapping Expedient (RESUME) to show that the standard acquisition leading to a clinical SWI dataset can be easily turned into a thorough qMRI protocol at the cost of a further 50% of the SWI scan time. The R1, [Formula: see text], proton density and magnetic susceptibility maps provided by the RESUME scheme alongside the SWI reconstruction exhibit high reproducibility and accuracy, and a submillimeter resolution is proven to be compatible with a total scan time of 7 minutes.

The common Dentex (Dentex dentex, Linnaeus 1758) has a significant economic importance and is a highly valued table fish in the Mediterranean region. The paucity of genetic information relating to sparids, despite their growing economic value, provides the impetus for exploring the mitogenomics of this fish group. Here, we sequenced D. dentex complete mitochondrial genome. The sequence is comprised of 16,652 bp and consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a 2 non-coding regions (D-loop and L-origin). The overall nucleotide composition is: 27.5% of A, 28.7% of C, 26.9% of T, and 16.9% of G.

The axillary seabream (Pagellus acarne, Risso 1827) belongs to the Sparidae family, order Perciformes. This high-valued commercial fish species is distributed along the northern and eastern Atlantic coasts from Norway to Senegal, and throughout the Mediterranean Sea. Its complete mitochondrial genome is 16,486 bp in length, consisting of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and 2 non-coding regions (D-loop, 808 bp and L-origin, 29 bp). Its overall base composition is A: 26,8%, C: 29,0%, G: 17.6%, and T: 26.6%.

The term ‘personalized medicine’ refers to a medical procedure that consists in the grouping of patients based on their predicted individual response to therapy or risk of disease. In oncologic patients, a ‘tailored’ therapeutic approach may potentially improve their survival and well-being by not only reducing the tumour, but also enhancing therapeutic response and minimizing the adverse effects. Diagnostic tests are often used to select appropriate and optimal therapies that rely both on patient genome and other molecular/cellular analysis. Several studies have shown that lifestyle and environmental factors can influence the epigenome and that epigenetic events may be involved in carcinogenesis. Thus, in addition to traditional biomarkers, epigenetic factors are raising considerable interest, because they could potentially be used as an excellent tool for cancer diagnosis and prognosis. In this review, we summarize the role of conventional cancer genetic biomarkers and their association with epigenomics. Furthermore, we will focus on the so-called ‘homeostatic biomarkers’ that result from the physiological response to cancer, emphasizing the concept that an altered ‘new’ homeostasis influence not only tumour environment, but also the whole organism.

Pancreatic ductal adenocarcinoma is currently one of the deadliest cancers with low overall survival rate. This disease leads to an aggressive local invasion and early metastases and is poorly responsive to treatment with chemotherapy or chemoradiotherapy. Several studies have shown that pancreatic cancer stem cells (PCSCs) play different roles in the regulation of drug resistance and recurrence in pancreatic cancer. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, is involved in the modulation of several biological activities ranging from invasion to metastases development, as well as drug resistance of pancreatic cancer. In this review, we synthesize the latest findings on the role of miRNAs in regulating different biological properties of pancreatic cancer stem cells.

The use of carbon monoxide (CO) in fresh fish has generated considerable debate. Carbon monoxide is used to treat fresh fish in order to retain its fresh red appearance for a longer period. It reacts with the oxy-myoglobin to form a fairly stable cherry red carboxy-myoglobin complex that may mask spoilage, because the CO-complex can be stable beyond the microbiological shelf life of the meat. The presence of CO in tuna fish (Thunnus Albacares) has been investigated by means of optical spectroscopy. Formation of the CO adduct can be easily detected by the combined analysis of electronic absorption spectra in their normal and second derivative modes, monitoring the intense Soret band at 420 nm. Samples were judged as CO treated when their levels were higher than 200 ng/g. Only two positive samples out of 29 analyzed were detected. The high level of uncertainty (0.30) of the method requires the use of more specific and sensitive methods for confirmatory analysis.

In susceptibility-weighted imaging (SWI), the high resolution required to obtain a proper contrast generation leads to a reduced signal-to-noise ratio (SNR). The application of a denoising filter to produce images with higher SNR and still preserve small structures from excessive blurring is therefore extremely desirable. However, as the distributions of magnitude and phase noise may introduce biases during image restoration, the application of a denoising filter is non-trivial. Taking advantage of the potential multispectral nature of MR images, a multicomponent approach using a Non-Local Means (MNLM) denoising filter may perform better than a component-by-component image restoration method. Here we present a new MNLM-based method (Multicomponent-Imaginary-Real-SWI, hereafter MIR-SWI) to produce SWI images with high SNR and improved conspicuity. Both qualitative and quantitative comparisons of MIR-SWI with the original SWI scheme and previously proposed SWI restoring pipelines showed that MIR-SWI fared consistently better than the other approaches. Noise removal with MIR-SWI also provided improvement in contrast-to-noise ratio (CNR) and vessel conspicuity at higher factors of phase mask multiplications than the one suggested in the literature for SWI vessel imaging. We conclude that a proper handling of noise in the complex MR dataset may lead to improved image quality for SWI data.

To characterize the anatomy of the venous outflow of the mouse brain using different imaging techniques. Ten C57/black male mice (age range: 7-8 weeks) were imaged with high-frequency Ultrasound, Magnetic Resonance Angiography and ex-vivo Microcomputed tomography of the head and neck. Under general anesthesia, Ultrasound of neck veins was performed with a 20 MHz transducer; head and neck Magnetic Resonance Angiography data were collected on 9.4 T or 7 T scanners, and ex-vivo Microcomputed tomography angiography was obtained by filling the vessels with a radiopaque inert silicone rubber compound. All procedures were approved by the local ethical committee. The dorsal intracranial venous system is quite similar in mice and humans. Instead, the mouse Internal Jugular Veins are tiny vessels receiving the sigmoid sinuses and tributaries from cerebellum, occipital lobe and midbrain, while the majority of the cerebral blood, i.e. from the olfactory bulbs and fronto-parietal lobes, is apparently drained through skull base connections into the External Jugular Vein. Three main intra-extracranial anastomoses, absent in humans, are: 1) the petrosquamous sinus, draining into the posterior facial vein, 2) the veins of the olfactory bulb, draining into the superficial temporal vein through a foramen of the frontal bone 3) the cavernous sinus, draining in the External Jugular Vein through a foramen of the sphenoid bone. The anatomical structure of the mouse cranial venous outflow as depicted by Ultrasound, Microcomputed tomography and Magnetic Resonance Angiography is different from humans, with multiple connections between intra- and extra-cranial veins.

Magnetic Resonance properties of tissues can be quantified in several respects: relaxation processes, density of imaged nuclei, magnetism of environmental molecules, etc. In this paper, we propose a new comprehensive approach to obtain 3D high resolution quantitative maps of arbitrary body districts, mainly focusing on the brain. The theory presented makes it possible to map longitudinal (R1), pure transverse (R2) and free induction decay ([Formula: see text]) rates, along with proton density (PD) and magnetic susceptibility (χ), from a set of fast acquisition sequences in steady-state that are highly insensitive to flow phenomena. A novel denoising scheme is described and applied to the acquired datasets to enhance the signal to noise ratio of the derived maps and an information theory approach compensates for biases from radio frequency (RF) inhomogeneities, if no direct measure of the RF field is available. Finally, the results obtained on sample brain scans of healthy controls and multiple sclerosis patients are presented and discussed.

Fishery products have always been an important food in Italy. In the past, increased consumption was mainly due to the good quality of the products, easiness of use and their beneficial effects on health. Recently, owing to the national financial crisis, there has been a decline in the consumption of fish. In fact, in 2013, according to data from ISMEA, the consumption of fresh fish suffered a sharp contraction (-5%). This decline also concerns anchovy (Engraulis encrasicolus). This species, partly because of its low price, is a mainstay of traditional Italian food. The aim of this study was to evaluate sensorial, chemical and microbiological properties of anchovy-based (Engraulis encrasicolus) products during storage at 4 and -20°C. Fresh anchovies, obtained from the wholesale fish market of Pozzuoli (Southern Italy) were cut into small pieces and hand-prepared using bread, eggs, cheese and lemon juice. Samples were analysed after 0, 2, 4, 6 and 8 days of storage at 4°C. An aliquot was quickly frozen and analysed after 34 days at -20°C. Sensory assessment, microbiological (specific spoilage organisms, Listeria spp. and Salmonella spp.) and chemical (histamine, total volatile basic nitrogen, trimethylamine, thiobarbituric acid, pH and aw) analyses were performed. Results showed that the shelf life of anchovy products was less than 5 days for the samples stored at 4°C. At -20°C, all anchovies preparations showed good sensory, microbiological and chemical properties for 34 days.

The purpose of this study is to compare different normal tissue complication probability (NTCP) models for predicting heart valve dysfunction (RVD) following thoracic irradiation.All patients from our institutional Hodgkin lymphoma survivors database with analyzable datasets were included (n = 90). All patients were treated with three-dimensional conformal radiotherapy with a median total dose of 32 Gy. The cardiac toxicity profile was available for each patient. Heart and lung dose-volume histograms (DVHs) were extracted and both organs were considered for Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP model fitting using maximum likelihood estimation. Bootstrap refitting was used to test the robustness of the model fit. Model performance was estimated using the area under the receiver operating characteristic curve (AUC).Using only heart-DVHs, parameter estimates were, for the LKB model: D50 = 32.8 Gy, n = 0.16 and m = 0.67; and for the RS model: D50 = 32.4 Gy, s = 0.99 and γ = 0.42. AUC values were 0.67 for LKB and 0.66 for RS, respectively. Similar performance was obtained for models using only lung-DVHs (LKB: D50 = 33.2 Gy, n = 0.01, m = 0.19, AUC = 0.68; RS: D50 = 24.4 Gy, s = 0.99, γ = 2.12, AUC = 0.66). Bootstrap result showed that the parameter fits for lung-LKB were extremely robust. A combined heart-lung LKB model was also tested and showed a minor improvement (AUC = 0.70). However, the best performance was obtained using the previously determined multivariate regression model including maximum heart dose with increasing risk for larger heart and smaller lung volumes (AUC = 0.82).The risk of radiation induced valvular disease cannot be modeled using NTCP models only based on heart dose-volume distribution. A predictive model with an improved performance can be obtained but requires the inclusion of heart and lung volume terms, indicating that heart-lung interactions are apparently important for this endpoint.

The heartbeat has been proposed as an intrinsic source of motion that can be used in combination with tagged Magnetic Resonance Imaging (MRI) to measure displacements induced in the liver as an index of liver stiffness. Optimizing a tagged MRI acquisition protocol in terms of sensitivity to these displacements, which are in the order of pixel size, is necessary to develop the method as a quantification tool for staging fibrosis. We reproduced a study of cardiac-induced strain in the liver at 3T and simulated tagged MR images with different grid tag patterns to evaluate the performance of the Harmonic Phase (HARP) image analysis method and its dependence on the parameters of tag spacing and grid angle. The Partial Volume Effect (PVE), T1 relaxation, and different levels of noise were taken into account. Four displacement fields of increasing intensity were created and applied to the tagged MR images of the liver. These fields simulated the deformation at different liver stiffnesses. An Error Index (EI) was calculated to evaluate the estimation accuracy for various parameter values. In the absence of noise, the estimation accuracy of the displacement fields increased as tag spacings decreased. EIs for each of the four displacement fields were lower at 0° and the local minima of the EI were found to correspond to multiples of pixel size. The accuracy of the estimation decreased for increasing levels of added noise; as the level increased, the improved estimation caused by decreasing the tag spacing tended to zero. The optimal tag spacing turned out to be a compromise between the smallest tag period that is a multiple of the pixel size and is achievable in a real acquisition and the tag spacing that guarantees an accurate liver displacement measure in the presence of realistic levels of noise.

Cl-IB-MECA is a selective A3 adenosine receptor agonist, which plays a crucial role in limiting tumor progression. In mice, Cl-IB-MECA administration enhances the anti-tumor T cell-mediated response. However, little is known about the activity of Cl-IB-MECA on CD8+ T cells. The aim of this study was to investigate the effect of ex vivo Cl-IB-MECA treatment of CD8+ T cells, adoptively transferred in melanoma-bearing mice. Adoptive transfer of Cl-IB-MECA-treated CD8+ T cells or a single administration of Cl-IB-MECA (20 ng/mouse) inhibited tumor growth compared with the control group and significantly improved mouse survival. This was associated with the release of Th1-type cytokines and a greater influx of mature Langerin+ dendritic cells (LCs) into the tumor microenvironment. CD8+ T cells treated with Cl-IB-MECA released TNF-α which plays a critical role in the therapeutic efficacy of these cells when injected to mice. Indeed, neutralization of TNF-α by a specific monoclonal Ab significantly blocked the anti-tumor activity of Cl-IB-MECA-treated T cells. This was due to the reduction in levels of cytotoxic cytokines and the presence of fewer LCs. In conclusion, these studies reveal that ex vivo treatment with Cl-IB-MECA improves CD8+ T cell adoptive immunotherapy for melanoma in a TNF-α-dependent manner.