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Background and Purpose: The development of Magnetic Resonance Imaging (MRI)-only Radiotherapy (RT) represents a significant advancement in the field. This study introduces a Deep Learning (DL) algorithm designed to quickly generate synthetic CT (sCT) images from low-field MR images in the brain, an area not yet explored. Methods: Fifty-six patients were divided into training (32), validation (8), and test (16) groups. A conditional Generative Adversarial Network (cGAN) was trained on pre-processed axial paired images. sCTs were validated using mean absolute error (MAE) and mean error (ME) calculated within the patient body. Intensity Modulated Radiation Therapy (IMRT) plans were optimised on simulation MRI and calculated considering sCT and original CT as electron density (ED) map. Dose distributions using sCT and CT were compared using global gamma analysis at different tolerance criteria (2 %/2mm and 3 %/3mm) and evaluating the difference in estimating different Dose Volume Histogram (DVH) parameters for target and organs at risk (OARs). Results: The network generated sCTs of each single patient in less than two minutes (mean time = 103 ± 41 s). For test patients, the MAE was 62.1 ± 17.7 HU, and the ME was −7.3 ± 13.4 HU. Dose parameters on sCTs were within 0.5 Gy of those on original CTs. Gamma passing rates 2 %/2mm, and 3 %/3mm criteria were 99.5 %±0.5 %, and 99.7 %±0.3 %, respectively. Conclusion: The proposed DL algorithm generates in less than 2 min accurate sCT images in the brain for online adaptive radiotherapy, potentially eliminating the need for CT simulation in MR-only workflows for brain treatments.

Abstract Multiple omics analyzes of Vaccinia virus (VACV) infection have defined molecular characteristics of poxvirus biology. However, little is known about the monkeypox (mpox) virus (MPXV) in humans, which has a different disease manifestation despite its high sequence similarity to VACV. Here, we perform an in-depth multi-omics analysis of the transcriptome, proteome, and phosphoproteome signatures of MPXV-infected primary human fibroblasts to gain insights into the virus-host interplay. In addition to expected perturbations of immune-related pathways, we uncover regulation of the HIPPO and TGF-β pathways. We identify dynamic phosphorylation of both host and viral proteins, which suggests that MAPKs are key regulators of differential phosphorylation in MPXV-infected cells. Among the viral proteins, we find dynamic phosphorylation of H5 that influenced the binding of H5 to dsDNA. Our extensive dataset highlights signaling events and hotspots perturbed by MPXV, extending the current knowledge on poxviruses. We use integrated pathway analysis and drug-target prediction approaches to identify potential drug targets that affect virus growth. Functionally, we exemplify the utility of this approach by identifying inhibitors of MTOR, CHUK/IKBKB, and splicing factor kinases with potent antiviral efficacy against MPXV and VACV.

Abstract Background Two isoforms of Phosphoinositide 3-kinase (PI3K), p110γ and p110δ, are predominantly expressed in leukocytes and represent attractive therapeutic targets for the treatment of allergic asthma. The study aim was to assess the impact of administration of an inhaled PI3Kγδ inhibitor (AZD8154) in a rat model of asthma. Methods Firstly, we checked that the tool compound, AZD8154, inhibited rat PI3K γ & δ kinases using rat cell-based assays. Subsequently, a time-course study was conducted in a rat model of asthma to assess PI3K activity in the lung and how it is temporally associated with other key transcription pathways and asthma like features of the model. Finally, the impact on lung dosed AZD8154 on target engagement, pathway specificity, airway inflammation and lung function changes was assessed. Results Data showed that AZD8154 could inhibit rat PI3K γ & δ isoforms and, in a rat model of allergic asthma the PI3K pathway was activated in the lung. Intratracheal administration of AZD8154 caused a dose related suppression PI3K pathway activation (reduction in pAkt) and unlike after budesonide treatment, STAT and NF-κB pathways were not affected by AZD8154. The suppression of the PI3K pathway led to a marked inhibition of airway inflammation and reduction in changes in lung function. Conclusion These data show that a dual PI3Kγδ inhibitor suppress key features of disease in a rat model of asthma to a similar degree as budesonide and indicate that dual PI3Kγδ inhibition may be an effective treatment for people suffering from allergic asthma.

Background: Prostate cancer (PCa) is the second most common cancer in men, and radiotherapy (RT) is one of the main treatment options. Although effective, RT can cause toxic side effects. The accurate prediction of dosimetric parameters, enhanced by advanced technologies and AI-based predictive models, is crucial to optimize treatments and reduce toxicity risks. This study aims to explore current methodologies for predictive dosimetric parameters associated with RT toxicity in PCa patients, analyzing both traditional techniques and recent innovations. Methods: A systematic review was conducted using the PubMed, Scopus, and Medline databases to identify dosimetric predictive parameters for RT in prostate cancer. Studies published from 1987 to April 2024 were included, focusing on predictive models, dosimetric data, and AI techniques. Data extraction covered study details, methodology, predictive models, and results, with an emphasis on identifying trends and gaps in the research. Results: After removing duplicate manuscripts, 354 articles were identified from three databases, with 49 shortlisted for in-depth analysis. Of these, 27 met the inclusion criteria. Most studies utilized logistic regression models to analyze correlations between dosimetric parameters and toxicity, with the accuracy assessed by the area under the curve (AUC). The dosimetric parameter studies included Vdose, Dmax, and Dmean for the rectum, anal canal, bowel, and bladder. The evaluated toxicities were genitourinary, hematological, and gastrointestinal. Conclusions: Understanding dosimetric parameters, such as DVH, Dmax, and Dmean, is crucial for optimizing RT and predicting toxicity. Enhanced predictive accuracy improves treatment effectiveness and reduces side effects, ultimately improving patients’ quality of life. Emerging artificial intelligence and machine learning technologies offer the potential to further refine RT in PCa by analyzing complex data, and enabling more personalized treatment approaches.

Astrocytes represent the most abundant cell type in the brain, where they play critical roles in synaptic transmission, cognition, and behavior. Recent discoveries show astrocytes are involved in synaptic dysfunction during Alzheimer’s disease (AD). AD patients have imbalanced cholesterol metabolism, demonstrated by high levels of side-chain oxidized cholesterol known as 27-hydroxycholesterol (27-OH). Evidence from our laboratory has shown that elevated 27-OH can abolish synaptic connectivity during neuromaturation, but its effect on astrocyte function is currently unclear. Our results suggest that elevated 27-OH decreases the astrocyte function in vivo in Cyp27Tg, a mouse model of brain oxysterol imbalance. Here, we report a downregulation of glutamate transporters in the hippocampus of CYP27Tg mice together with increased GFAP. GLT-1 downregulation was also observed when WT mice were fed with high-cholesterol diets. To study the relationship between astrocytes and neurons, we have developed a 3D co-culture system that allows all the cell types from mice embryos to differentiate in vitro. We report that our 3D co-cultures reproduce the effects of 27-OH observed in 2D neurons and in vivo. Moreover, we found novel degenerative effects in astrocytes that do not appear in 2D cultures, together with the downregulation of glutamate transporters GLT-1 and GLAST. We propose that this transporter dysregulation leads to neuronal hyperexcitability and synaptic dysfunction based on the effects of 27-OH on astrocytes. Taken together, these results report a new mechanism linking oxysterol imbalance in the brain and synaptic dysfunction through effects on astrocyte function.

Artificial Intelligence (AI) is revolutionising many aspects of radiotherapy (RT), opening scenarios that were unimaginable just a few years ago. The aim of this study is to propose a Deep Leaning (DL) approach able to quickly generate synthetic Computed Tomography (CT) images from low-dose Cone Beam CT (CBCT) acquired on a modern linear accelerator integrating AI. Methods: A total of 53 patients treated in the pelvic region were enrolled and split into training (30), validation (9), and testing (14). A Generative Adversarial Network (GAN) was trained for 200 epochs. The image accuracy was evaluated by calculating the mean and mean absolute error (ME and ME) between sCT and CT. RT treatment plans were calculated on CT and sCT images, and dose accuracy was evaluated considering Dose Volume Histogram (DVH) and gamma analysis. Results: A total of 4507 images were selected for training. The MAE and ME values in the test set were 36 ± 6 HU and 7 ± 6 HU, respectively. Mean gamma passing rates for 1%/1 mm, 2%/2 mm, and 3%/3 mm tolerance criteria were respectively 93.5 ± 3.4%, 98.0 ± 1.3%, and 99.2 ± 0.7%, with no difference between curative and palliative cases. All the DVH parameters analysed were within 1 Gy of the difference between sCT and CT. Conclusion: This study demonstrated that sCT generation using the DL approach is feasible on low-dose CBCT images. The proposed approach can represent a valid tool to speed up the online adaptive procedure and remove CT simulation from the RT workflow.

Abstract Introduction Adjuvant radiation therapy (RT) following primary surgery in women affected by early breast cancer (EBC) plays a central role in reducing local recurrences and overall mortality. The FAST‐FORWARD trial recently demonstrated that 1‐week hypofractionated adjuvant RT is not inferior to the standard schedule in terms of local relapse, cosmetic outcomes and toxicity. The aim of this in silico study was to evaluate the dosimetric aspects of a 1‐week RT course, administered through volumetric modulated arc therapy (VMAT), compared with traditional three‐dimensional conformal radiation therapy (3D‐CRT) with tangential fields. Methods Patients affected by left‐side EBC undergoing adjuvant RT were selected. ESTRO guidelines for the clinical target volume (CTV) delineation and FAST‐FORWARD protocol for CTV to planning target volume (PTV) margin definition were followed. Total prescribed dose was 26 Gy in five fractions. The homogeneity index (HI) and the global conformity index (GCI) were taken into account for planning and dose distribution optimisation purposes. Both 3D‐CRT tangential fields and VMAT plans were generated for each patient. Results The analysis included 21 patients. PTV coverage comparison between 3D‐CRT and VMAT plans showed significant increases for GCI (P

Background: The favorable role of SBRT for lymph-nodal oligometastases from prostate cancer has been reported by several retrospective and prospective experiences, suggesting a more indolent natural history of disease when compared to patients with bone oligometastases. This retrospective multicenter study evaluates the outcomes of a cohort of patients treated with stereotactic body radiotherapy for lymph-nodal oligometastases. Methods: Inclusion criteria were up to five lymph-nodal oligometastases detected either with Choline-PET or PSMA-PET in patients naïve for ADT or already ongoing with systemic therapy and at least 6 Gy per fraction for SBRT. Only patients with exclusive lymph-nodal disease were included. The primary endpoint of the study was LC; a toxicity assessment was retrospectively performed following CTCAE v4.0. Results: A total of 100 lymph-nodal oligometastases in 69 patients have been treated with SBRT between April 2015 and November 2022. The median age was 73 years (range, 60–85). Oligometastatic disease was mainly detected with Choline-PET in 47 cases, while the remaining were diagnosed using PSMA-PET, with most of the patients treated to a single lymph-nodal metastasis (48/69 cases), two in 14 cases, and three in the remaining cases. The median PSA prior to SBRT was 1.35 ng/mL (range, 0.3–23.7 ng/mL). Patients received SBRT with a median total dose of 35 Gy (range, 30–40 Gy) in a median number of 5 (range, 3–6) fractions. With a median follow-up of 16 months (range, 7–59 months), our LC rates were 95.8% and 86.3% at 1 and 2 years. DPFS rates were 90.4% and 53.4%, respectively, at 1 and 2 years, with nine patients developing a sequential oligometastatic disease treated with a second course of SBRT. Polymetastatic disease-free survival (PMFS) at 1 and 2 years was 98% and 96%. Six patients needed ADT after SBRT for a median time of ADT-free survival of 15 months (range, 6–22 months). The median OS was 16 months (range, 7–59) with 1- and 2-year rates of both 98%. In multivariate analysis, higher LC rates and the use of PSMA-PET were related to improved DPFS rates, and OS was significantly related to a lower incidence of distant progression. No G3 or higher adverse events were reported. Conclusions: In our experience, lymph-nodal SBRT for oligometastatic prostate cancer is a safe and effective option for ADT delay with no severe toxicity.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unmet medical need. It is characterized by formation of scar tissue leading to a progressive and irreversible decline in lung function. IPF is associated with repeated injury, which may alter the composition of the extracellular matrix (ECM). Here, we demonstrate that IPF patient–derived pulmonary ECM drives profibrotic response in normal human lung fibroblasts (NHLF) in a 3D spheroid assay. Next, we reveal distinct alterations in composition of the diseased ECM, identifying potentially novel associations with IPF. Growth differentiation factor 15 (GDF15) was identified among the most significantly upregulated proteins in the IPF lung–derived ECM. In vivo, GDF15 neutralization in a bleomycin-induced lung fibrosis model led to significantly less fibrosis. In vitro, recombinant GDF15 (rGDF15) stimulated α smooth muscle actin (αSMA) expression in NHLF, and this was mediated by the activin receptor-like kinase 5 (ALK5) receptor. Furthermore, in the presence of rGDF15, the migration of NHLF in collagen gel was reduced. In addition, we observed a cell type–dependent effect of GDF15 on the expression of cell senescence markers. Our data suggest that GDF15 mediates lung fibrosis through fibroblast activation and differentiation, implicating a potential direct role of this matrix-associated cytokine in promoting aberrant cell responses in disease.

Host proteins sense viral products and induce defence mechanisms, particularly in immune cells. Using cell-free assays and quantitative mass spectrometry, we determined the interactome of capsid-host protein complexes of herpes simplex virus and identified the large dynamin-like GTPase myxovirus resistance protein B (MxB) as an interferon-inducible protein interacting with capsids. Electron microscopy analyses showed that cytosols containing MxB had the remarkable capability to disassemble the icosahedral capsids of herpes simplex viruses and varicella zoster virus into flat sheets of connected triangular faces. In contrast, capsids remained intact in cytosols with MxB mutants unable to hydrolyse GTP or to dimerize. Our data suggest that MxB senses herpesviral capsids, mediates their disassembly, and thereby restricts the efficiency of nuclear targeting of incoming capsids and/or the assembly of progeny capsids. The resulting premature release of viral genomes from capsids may enhance the activation of DNA sensors, and thereby amplify the innate immune responses.

Introduction: Pancreatic cancer (PC) is one of the most aggressive tumours, and better risk stratification among patients is required to provide tailored treatment. The meaning of radiomics and texture analysis as predictive techniques are not already systematically assessed. The aim of this study is to assess the role of radiomics in PC. Methods: A PubMed/MEDLINE and Embase systematic review was conducted to assess the role of radiomics in PC. The search strategy was ‘radiomics [All Fields] AND (“pancreas” [MeSH Terms] OR “pancreas” [All Fields] OR “pancreatic” [All Fields])’ and only original articles referred to PC in humans in the English language were considered. Results: A total of 123 studies and 183 studies were obtained using the mentioned search strategy on PubMed and Embase, respectively. After the complete selection process, a total of 56 papers were considered eligible for the analysis of the results. Radiomics methods were applied in PC for assessment technical feasibility and reproducibility aspects analysis, risk stratification, biologic or genomic status prediction and treatment response prediction. Discussion: Radiomics seems to be a promising approach to evaluate PC from diagnosis to treatment response prediction. Further and larger studies are required to confirm the role and allowed to include radiomics parameter in a comprehensive decision support system.

INTROUDCTION Bullous pemphigoid (BP) is a common autoimmune bullous disease generally occurring in elderly patients. Itchy and tense blisters on normal skin or erythematous and edematous lesions on the trunk and extremities usually characterize BP. Trigger factors are still unclear while several case reports suggest a potential role of radiotherapy (RT) as BP trigger for disease onset or recrudescence. A review was performed in order to provide an update of literature. A case report of a patient affected by BP undergoing two radiotherapy courses for a primary breast cancer was also reported. MATERIALS AND METHODS A comprehensive review of the published literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. The review included studies describing BP and its relationships with RT treatments. RESULTS A total of 13 articles were reviewed. Studies characteristics analysis resulted in eleven case reports, one case series and one large-scale case–control study. CONCLUSIONS Literature update confirms the existence of a reasonable connection between RT and BP. Case report showed that a multidisciplinary management seems to assure the feasibility of RT in patients affected by BP, not depriving them of standard therapeutic opportunities.

ObjectiveRadiotherapy (RT) in the head and neck (H&N) site are undoubtedly the most challenging treatments for patients. Older and frail patients are not always able to tolerate it, and there are still no clear guidelines on the type of treatments to be preferred for them. The recommendations for Risk-Adapted H&N Cancer Radiation Therapy during the coronavirus disease 2019 (COVID-19) pandemic provided by the ASTRO-ESTRO consensus statement achieved a strong agreement about hypofractionated RT (HFRT). A systematic literature review was conducted in order to evaluate the feasibility and safety of HFRT for older patients affected by H&N malignancies.Materials and MethodsA systematic database search was performed on PubMed and Embase according to Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guidelines. Original studies, case series, and case reports describing the use of HFRT (with at least 2.2 Gy fractions) in patients with mean age ≥65 years were included. The analysis was based on the type of study, number of patients, mean age, tumor site, histology, performance status (PS), RT details, concomitant chemotherapy (CT), and described clinical outcomes. All the reported doses have been calculated in equivalent dose in 2 Gy fractions (EQD2) and biologically effective dose (BED) using α/β = 10 Gy or α/β = 12 Gy.ResultsWe selected 17 papers that met the inclusion criteria and divided them in 4 categories: 6 articles analyze HFRT performed twice daily in repeated cycles, 3 once a day in repeated cycles, 4 in alternative days, and the last 4 in consecutive days.ConclusionHFRT seems to be a good treatment with an acceptable prolonged disease control. In older patients fit for radical treatments, a 55 Gy in 20 fractions regimen can be proposed as a valid alternative to the standard fractionated RT, but there are a multitude of hypofractionated regimens, ranging from single fraction, quad shot, and 1-, 2-, 3-, 4-, and 5-week schedules that all may be appropriate. The correct regimen for a patient depends on many factors, and it represents the result of a more specific and complex decision.

In the management of prostate cancer (PCa), correct staging is crucial in order to assess the right therapeutic approach. [18F]Choline PET/CT has been shown to provide more accurate staging information than conventional imaging approaches. The aim of this paper is to provide a real practice demonstration of the impact of [18F]Choline PET/CT on low-risk prostate cancer staging and clinical management. We report a 64-year-old man with biochemical PCa recurrence diagnosis after transurethral resection of the prostate. The patient, after the detection of an increased level of PSA, underwent multi-parametric prostate magnetic resonance imaging (mpMRI) that did not show evidence of disease. The patient was admitted to perform [18F]Choline PET/CT that showed a macroscopic prostate recurrence. Patient underwent photon external beam radiation therapy (EBRT) treatment, and [18F]Choline PET/CT was also used to define treatment volumes. At 3- and 6-month clinical follow-up evaluations, no late toxicity was detected and a significant reduction in PSA value was shown. Therefore, our case highlights the potential usefulness of [18F]Choline PET/CT for the staging of low-risk prostate cancer and its impact on the management and quality of life of such patients. The presented case should urge the scientific community to enhance larger and multicentric studies, assessing more extensively the potential impact of [18F]Choline PET/CT in this clinical scenario.

Viral infections have a large impact on society, leading to major human and economic losses and even global instability. So far, many viral infections, including human cytomegalovirus (HCMV) infection, are treated with a small repertoire of drugs, often accompanied by the occurrence of resistant mutants.

The aim of this study is to investigate the role of Delta Radiomics analysis in the prediction of one-year local control (1yLC) in patients affected by locally advanced pancreatic cancer (LAPC) and treated using Magnetic Resonance guided Radiotherapy (MRgRT). A total of 35 patients from two institutions were enrolled: A 0.35 Tesla T2*/T1 MR image was acquired for each case during simulation and on each treatment fraction. Physical dose was converted in biologically effective dose (BED) to compensate for different radiotherapy schemes. Delta Radiomics analysis was performed considering the gross tumour volume (GTV) delineated on MR images acquired at BED of 20, 40, and 60 Gy. The performance of the delta features in predicting 1yLC was investigated in terms of Wilcoxon Mann–Whitney test and area under receiver operating characteristic (ROC) curve (AUC). The most significant feature in predicting 1yLC was the variation of cluster shade calculated at BED = 40 Gy, with a p-value of 0.005 and an AUC of 0.78 (0.61–0.94). Delta Radiomics analysis on low-field MR images might play a promising role in 1yLC prediction for LAPC patients: further studies including an external validation dataset and a larger cohort of patients are recommended to confirm the validity of this preliminary experience.

Background: Recent studies have highlighted the potentialities of a radiobiological parameter, the early regression index (ERITCP), in the treatment response prediction for rectal cancer patients treated with chemoradiotherapy followed by surgery. The aim of this study is to evaluate the performance of this parameter in predicting pathological complete response (pCR) in the context of low field MR guided radiotherapy (MRgRT) for cervical cancer (CC). Methods: A total of 16 patients affected by CC were enrolled. All patients underwent a MRgRT treatment, with prescription of 50.6 Gy in 22 fractions. A daily MR acquisition was performed at simulation and on each treatment fraction. Gross tumor volume (GTV) was delineated on the MR images acquired at the following biological effective dose (BED) levels: 14, 28, 42, 54 and 62 Gy. The ERITCP was calculated at the different BED levels and its predictive performance was quantified in terms of receiver operating characteristic (ROC) curve. Results: pCR was observed in 11/16 cases. The highest discriminative power of ERITCP was reported when a BED value of 28 Gy is reached, obtaining an area under curve (AUC) of 0.84. Conclusion: This study confirmed ERITCP as a promising response biomarker also for CC, although further studies with larger cohort of patients are recommended.

Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER–mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD.

Spinal muscular atrophy (SMA) is a severe neuromuscular disease, the most common in infancy, and the third one among young people under 18 years. The major pathological landmark of SMA is a selective degeneration of lower motor neurons, resulting in progressive skeletal muscle denervation, atrophy, and paralysis. Recently, it has been shown that specific or general changes in the activity of ribonucleoprotein containing micro RNAs (miRNAs) play a role in the development of SMA. Additionally miRNA-206 has been shown to be required for efficient regeneration of neuromuscular synapses after acute nerve injury in an ALS mouse model. Therefore, we correlated the morphology and the architecture of the neuromuscular junctions (NMJs) of quadriceps, a muscle affected in the early stage of the disease, with the expression levels of miRNA-206 in a mouse model of intermediate SMA (SMAII), one of the most frequently used experimental model. Our results showed a decrease in the percentage of type II fibers, an increase in atrophic muscle fibers and a remarkable accumulation of neurofilament (NF) in the pre-synaptic terminal of the NMJs in the quadriceps of SMAII mice. Furthermore, molecular investigation showed a direct link between miRNA-206-HDAC4-FGFBP1, and in particular, a strong up-regulation of this pathway in the late phase of the disease. We propose that miRNA-206 is activated as survival endogenous mechanism, although not sufficient to rescue the integrity of motor neurons. We speculate that early modulation of miRNA-206 expression might delay SMA neurodegenerative pathway and that miRNA-206 could be an innovative, still relatively unexplored, therapeutic target for SMA.

Several evidences suggest that the position of palmitic acid (PA) in dietary triacylglycerol (TAG) influences different biological functions. We aimed at evaluating whether dietary fat with highly enriched (87%) PA in sn-2 position (Hsn-2 PA), by increasing PA incorporation into tissue phospholipids (PL), modifies fatty acid profile and biosynthesis of fatty acid-derived bioactive lipids, such as endocannabinoids and their congeners.Rats were fed for 5 weeks diets containing Hsn-2 PA or fat with PA randomly distributed in TAG with 18.8% PA in sn-2 position (Lsn-2 PA), and similar total PA concentration. Fatty acid profile in different lipid fractions, endocannabinoids and congeners were measured in intestine, liver, visceral adipose tissue, muscle and brain.Rats on Hsn-2 PA diet had lower levels of anandamide with concomitant increase of its congener palmitoylethanolamide and its precursor PA into visceral adipose tissue phospholipids. In addition, we found an increase of oleoylethanolamide, an avid PPAR alpha ligand, in liver, muscle and brain, associated to higher levels of its precursor oleic acid in liver and muscle, probably derived by elongation and further delta 9 desaturation of PA. Changes in endocannabinoids and congeners were associated to a decrease of circulating TNF alpha after LPS challenge, and to an improved feed efficiency.Dietary Hsn-2 PA, by modifying endocannabinoids and congeners biosynthesis in different tissues may potentially concur in the physiological regulation of energy metabolism, brain function and body fat distribution.

Several microalgae of the genus Alexandrium (Alexandrium minutum and Alexandrium catenelle) can produce an algal biotoxin, the paralytic shellfish poison (PSP) that can be accumulated in the shellfish edible tissues making them hazardous to the consumer’s health. In this paper we report i) the results of PSP toxins survey carried out by mouse bioassays (mouse test AOAC 958.08) on 7457 samples of bivalve molluscs farmed in Sardinia and in other European countries and marketed in Sardinia region from 2002 to 2011, and ii) the management of positive cases. Based on our experience it is very important to strictly apply the planned activities in order to prevent any risk and to protect the consumer’s and producer’s health.

Loss of the survival motor neuron gene (SMN1) is responsible for spinal muscular atrophy (SMA), the most common inherited cause of infant mortality. Even though the SMA phenotype is traditionally considered as related to spinal motor neuron loss, it remains debated whether the specific targeting of motor neurons could represent the best therapeutic option for the disease. We here investigated, using stereological quantification methods, the spinal cord and cerebral motor cortex of ∆7 SMA mice during development, to verify extent and selectivity of motor neuron loss. We found progressive post-natal loss of spinal motor neurons, already at pre-symptomatic stages, and a higher vulnerability of motor neurons innervating proximal and axial muscles. Larger motor neurons decreased in the course of disease, either for selective loss or specific developmental impairment. We also found a selective reduction of layer V pyramidal neurons associated with layer V gliosis in the cerebral motor cortex. Our data indicate that in the ∆7 SMA model SMN loss is critical for the spinal cord, particularly for specific motor neuron pools. Neuronal loss, however, is not selective for lower motor neurons. These data further suggest that SMA pathogenesis is likely more complex than previously anticipated. The better knowledge of SMA models might be instrumental in shaping better therapeutic options for affected patients.

Acute primary open angle glaucoma is an optic neuropathy characterized by the elevation of intraocular pressure, which causes retinal ischemia and neuronal death. Rat ischemia/reperfusion enhances endocytosis of both horseradish peroxidase (HRP) or fluorescent dextran into ganglion cell layer (GCL) neurons 24 h after the insult. We investigated the activation of autophagy in GCL-neurons following ischemia/reperfusion, using acid phosphatase (AP) histochemistry and immunofluorescence against LC3 and LAMP1. Retinal I/R lead to the appearance of AP-positive granules and LAMP1-positive vesicles 12 and 24 h after the insult, and LC3 labelling at 24 h, and induced a consistent retinal neuron death. At 48 h the retina was negative for autophagic markers. In addition, Western Blot analysis revealed an increase of LC3 levels after damage: the increase in the conjugated, LC3-II isoform is suggestive of autophagic activity. Inhibition of autophagy by 3-methyladenine partially prevented death of neurons and reduces apoptotic markers, 24 h post-lesion. The number of neurons in the GCL decreased significantly following I/R (I/R 12.21±1.13 vs controls 19.23±1.12 cells/500 µm); this decrease was partially prevented by 3-methyladenine (17.08±1.42 cells/500 µm), which potently inhibits maturation of autophagosomes. Treatment also prevented the increase in glial fibrillary acid protein immunoreactivity elicited by I/R. Therefore, targeting autophagy could represent a novel and promising treatment for glaucoma and retinal ischemia.