The contribution of the 1H-MRS lipid signal to cervical cancer prognosis: a preliminary study

Background The aim of this study was to investigate the role of the lipid peak derived from H-1 magnetic resonance (MR) spectroscopy in assessing cervical cancer prognosis, particularly in assessing response to neoadjuvant chemotherapy (NACT) of locally advanced cervical cancer (LACC). Methods We enrolled 17 patients with histologically proven cervical cancer who underwent 3-T MR imaging at baseline. In addition to conventional imaging sequences for pelvic assessment, the protocol included a single-voxel point-resolved spectroscopy (PRESS) sequence, with repetition time of 1,500 ms and echo times of 28 and 144 ms. Spectra were analysed using the LCModel fitting routine, thus extracting multiple metabolites, including lipids (Lip) and total choline (tCho). Patients with LACC were treated with NACT and reassessed by MRI at term. Based on tumour volume reduction, patients were classified as good responder (GR; tumour volume reduction > 50%) and poor responder or nonresponder (PR-or-NR; tumour volume reduction <= 50%). Results Of 17 patients, 11 were LACC. Of these 11, only 6 had both completed NACT and had good-quality H-1-MR spectra; 3 GR and 3 PR-or-NR. A significant difference in lipid values was observed in the two groups of patients, particularly with higher Lip values and higher Lip/tCho ratio in PR-NR patients (p =0.040). A significant difference was also observed in choline distribution (tCho), with higher values in GR patients (p = 0.040). Conclusions Assessment of lipid peak at H-1-MR spectroscopy could be an additional quantitative parameter in predicting the response to NACT in patients with LACC

Study of the effect of different breast implant surfaces on capsule formation and host inflammatory response in an animal model

Background: Breast implants are biomaterials eliciting a physiological and mandatory foreign body response. Objectives: The authors designed an animal study to investigate the impact of different implant surfaces on the formation of the periprosthetic capsule, the inflammatory response, and the cellular composition. Methods: The authors implanted 1 scaled-down version of breast implants by different manufactures on 70 female Sprague Dawley rats. Animals were divided into 5 groups of 14 animals. Group A received a smooth implant (Ra ≈ 0.5 µm) according to the ISO 14607-2018 classification, Group B a smooth implant (Ra ≈ 3.2 µm), Group C a smooth implant (Ra ≈ 5 µm), Group D a macrotextured implant (Ra ≈ 62 µm), and Group E a macrotextured implant (Ra ≈ 75 µm). At 60 days, all animals received a magnetic resonance imaging (MRI), and 35 animals were killed and their capsules sent for histology (capsule thickness, inflammatory infiltrate) and immunohistochemistry analysis (cellular characterization). The remaining animals repeated the MRI at 120 days and were killed following the same protocol. Results: MRI showed a thinner capsule in the smooth implants (Groups A-C) at 60 days (P < .001) but not at 120 days (P = .039), confirmed with histology both at 60 days (P = .005) and 120 days (P < .001). Smooth implants (Groups A-C) presented a mild inflammatory response at 60 days that was maintained at 120 days and a high M2-Macrophage concentration (anti-inflammatory). Conclusions: Our study confirms that smooth implants form a thinner capsule, inferior inflammatory infiltrate, and a cellular composition that indicates a mild host inflammatory response. A new host inflammatory response classification is elaborated classifying breast implants into mild, moderate, and high

the role of molecular and imaging biomarkers in the evaluation of inflammation in oncology

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Mice repeatedly exposed to Group-A \u3b2-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon

Repeated exposure to Group-A \u3b2-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities

Developing and validating in vivo 1H MRS methodology for monitoring tumour growth and metabolism

SIGLEAvailable from British Library Document Supply Centre- DSC:DXN055509 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Prenatal stress and peripubertal stimulation of the endocannabinoid system differentially regulate emotional responses and brain metabolism in mice.

The central endocannabinoid system (ECS) and the hypothalamic-pituitary-adrenal-axis mediate individual responses to emotionally salient stimuli. Their altered developmental adjustment may relate to the emergence of emotional disturbances. Although environmental influences regulate the individual phenotype throughout the entire lifespan, their effects may result particularly persistent during plastic developmental stages (e.g. prenatal life and adolescence). Here, we investigated whether prenatal stress--in the form of gestational exposure to corticosterone supplemented in the maternal drinking water (100 mg/l) during the last week of pregnancy--combined with a pharmacological stimulation of the ECS during adolescence (daily fatty acid amide hydrolase URB597 i.p. administration--0.4 mg/kg--between postnatal days 29-38), influenced adult mouse emotional behaviour and brain metabolism measured through in vivo quantitative magnetic resonance spectroscopy. Compared to control mice, URB597-treated subjects showed, in the short-term, reduced locomotion and, in the long term, reduced motivation to execute operant responses to obtain palatable rewards paralleled by reduced levels of inositol and taurine in the prefrontal cortex. Adult mice exposed to prenatal corticosterone showed increased behavioural anxiety and reduced locomotion in the elevated zero maze, and altered brain metabolism (increased glutamate and reduced taurine in the hippocampus; reduced inositol and N-Acetyl-Aspartate in the hypothalamus). Present data further corroborate the view that prenatal stress and pharmacological ECS stimulation during adolescence persistently regulate emotional responses in adulthood. Yet, whilst we hypothesized these factors to be interactive in nature, we observed that the consequences of prenatal corticosterone administration were independent from those of ECS drug-induced stimulation during adolescence

Social withdrawal and gambling-like profile after lentiviral manipulation of DAT expression in the rat accumbens

Dysfunction of brain dopamine transporter (DAT) has been associated with sensation seeking and impulse-control disorders. We recently generated a new animal model by stereotaxical inoculation of lentiviral vectors, which allowed localized intra-accumbal delivery of modulators for DAT gene: GFP (green fluorescent protein) control, silencers (Sil), a regulatable enhancer (DAT+), or both (DAT+Sil). Wistar male rats were followed both for socio-emotional profiles and for propensity to seek risky, uncertain rewards. Elevated anxiety and affiliation towards an unfamiliar partner emerged in Sil rats. Interestingly, in DAT+Sil rats (and Sil rats to a lesser extent) levels of playful social interaction were markedly reduced compared to controls. These DAT+Sil rats displayed a marked ‘gambling-like’ profile (i.e. preference for a large/uncertain over a small/sure reward), which disappeared upon doxycycline-induced switch-off onto DAT enhancer, but consistently reappeared with doxycycline removal. MRI-guided ¹H-MRS (at 4.7 T) examinations in vivo (under anaesthesia) revealed changes in the bioenergetic metabolites (phosphocreatine and total creatine) for DAT+Sil rats, indicating a functional up-regulation of dorsal striatum (Str) and conversely a down-regulation of ventral striatum (i.e. nucleus accumbens, NAc). A combined profile of (1) enhanced proneness to gambling and (2) strong social withdrawal is thus associated with altered DAT-induced balance within forebrain dopamine systems. In fact, risk of developing a gambling-prone, social-avoidant psychopathology might be associated with (1) dominant semi-automatic strategies and/or habits, developed within Str circuits, and (2) reduced NAc function, with poorer feedback adjustment on decisions by aversive experiences

Effects of palmitoylethanolamide on the onset and progression of the pathology on a triple transgene mouse model of Alzheimer disease.

Alzheimer disease (AD) is the most common form of neurodegenerative dementias where the major pathogenic mechanisms remain to be clarified. Data from animal models and human autopsy revealed that reactive gliosis might exert a key pathogenetic role in AD. It is reasonable to assume that early combination of neuroprotective and anti-inflammatory treatments aimed at restoring astrocyte functions may represent an appropriate approach to treat AD. PEA (palmitoylethanolamide) is a naturally occurring amide of ethanolamine and palmitic acid, abundant in the CNS, and produced by glial cells, studied for its anti-inflammatory and neuroprotective effects. In the present work we exploited the availability of a transgenic model of AD (3xTg-AD) harboring three mutant human genes (betaAPPSwe, PS1M146V, tauP301L) to investigate if chronic PEA treatment might modulate the onset and the progression of Abeta and tau pathologies. The 3xTg-AD mice develop amyloid plaques and neurofibrillary pathology in AD-relevant brain regions (Hip, cortex) and mimic the disease progression in humans. An integrated approach, involving in vivo MRS and histological studies were used. The experimental strategy involved a longitudinal ageing study examining metabolic alteration and relating any changes with indices of brain pathology taken from a subset of mice killed at 6 and 12 months of age. The experiment compared 3xTg-AD mice at 6 (n=11) and 12 (n=16) months of age and wildtype controls (n=13 and n=14, for 6 and 12 months, respectively). Animals were treated with chronic PEA administration and then undergo MRI and MRS scanning (VARIAN Inova MRI/MRS system, 4.7T) to evaluate genotype- and treatment- induced differences in brain metabolism. Parallel RT-PCR and Western blot analyses have been also performed. Quantitative MRS analyses indicate that PEA treatment affects brain metabolism. Our findings are supported by parallel RT-PCR and Western blot analyses. The current investigation provides evidence that PEA rescues altered molecular pathways that can mimic some traits of AD. Considering the safety and tolerability of PEA in humans, our findings offer new opportunity in AD treatment

Metabolic and morphological characterization of the triple transgene mouse model of Alzheimer disease: effects of palmitoylethanolamide on the onset and progression of the AD-pathology

Synopsis Alzheimer disease (AD) is is characterized clinically by progressive cognitive decline, and pathologically by the presence in the brain of senile plaques composed primarily of amyloid-beta peptide and neurofibrillary tangles containing hyperphosphorylated tau protein. Here we investigated the effects of a naturally occurring amide of ethanolamine and palmitic acid (PEA), abundant in the CNS to contrast the AD phenotype in triple transgene (PS1, APP and Tau) mice model, by in vivo 1H MRI and MRS and histology. Our data indicate that PEA treatment affects brain metabolism as a function of age and that PEA rescues altered molecular pathways that can mimic some traits of AD. Introduction -AD is the most common form of neurodegenerative dementias.1 Amyloid-beta (Abeta) deposition in senile plaques, neurofibrillary tangle formation and neuro-inflammation are the major pathogenic mechanisms that remain to be clarified. Data from animal models and human autopsy revealed that reactive gliosis might exert a key pathogenetic role in AD.2 On the basis of these considerations, it is reasonable to assume that early combination of neuroprotective and anti-inflammatory treatments aimed at restoring astrocyte functions may represent an appropriate approach to treat AD.3 PEA is a naturally occurring amide of ethanolamine and palmitic acid, abundant in the CNS, and produced by glial cells,4 studied for its anti-inflammatory and neuroprotective effects.3,5-8 Purpose - In the present work we exploited the availability of a transgenic model of AD (3xTg-AD) harboring three mutant human genes (betaAPPSwe, PS1M146V, tauP301L) to investigate if chronic PEA treatment might modulate the onset and the progression of Abeta and tau pathologies. The 3xTg-AD mice develop amyloid plaques and neurofibrillary pathology in AD-relevant brain regions (Hip, cortex) and mimic the disease progression in humans.9-11 Methods - An integrated approach, involving histological and spectroscopic studies were used. The main experimental strategy involved a longitudinal ageing study examining metabolic alteration and relating any changes with indices of brain pathology taken from a subset of mice killed at 6 and 12 months of age. The experiment compared 6 (n=11) and 12 months of age (n=16) 3xTg-AD mice and wildtype controls (wt n=13 and n=14, for 6 and 12 months, respectively). Chronic PEA treatment were given to evaluate its impact on the onset of the neuropathology. In particular, 3-month-old mice were continuously infused (subcutaneously) up to 90 days via osmotic mini-pumps with 10mg/kg of PEA and vehicle. Moreover, in order to elucidate whether the progression of Abeta and tau pathologies are impacted by the PEA administration, another set of animals at 9 months of age were chronically treated as previously described and tested until they reach 12 months of age. At the end of treatment animals undergo MRI and MRS scanning to evaluate genotype- and treatment- induced differences in brain metabolism. MR examinations were performed on VARIAN Inova MRI/MRS system (4.7T) and a combination of volume and surface coil (RAPID Biomedical). Multislice fast spin-echo (TR/TEeff=3000/70ms, ns=2, slice thickness 1mm, matrix 128x256) sagittal images were acquired to localise the regions of interest. Single-voxel localised 1H MR spectra (PRESS,TR/TE=4000/23ms, ns=256) were collected from: prefrontal cortex (PFC), 10.8ml and hippocampus (Hip), 9.5ml. Spectra were analysed by using LCModel program and unsuppressed water signal as reference.12 Statistical analysis was performed by using ANOVA (2x2 genotype and treatment). Results and Discussion – Quantitative MRS analyses and their significant differences due to genotype or treatment are summarized in Fig.1. In PFC at 6 months post-hoc analyses showed increased Ins in 3xTg-AD with respect to wt in both PEA- and vehicle-treated mice, an increase of tCr in vehicle-treated mice and of Tau in PEA-treated mice. At 12 months PEA effect was observed in all mice as an increase of tCr, and as an increase of Ins and Tau in 3xTG-AD mice only. In Hip at 6 months post-hoc analyses revealed a tCho increase, as PEA effect, in 3xTg-AD only mice. At 12 month, an increase of Glu was observed in 3xTg-AD with respect to wt mice. Our studies show that PEA treatment increase tCr in the PFC in the 3xTg-AD mice suggesting a change in energy metabolism. The apparent paradox of Ins decrease at 12 months in 3xTg-AD with respect to 6 months, could be not directly associated with the occurrence of Abeta, but associated with a change in the balance of neuronal/glial contributions. In fact, at 6 months the higher level of Ins of 3xTg-AD with respect to WT mice could be due to an increase of microglia and/or astrocytes activity, while at 12 months PEA could help to restore the original neuronal/glial balance.13 Our findings are supported by parallel RT-PCR and Western blot analyses. In 6 months old mice, an increase of markers related to glia activation and neuroinflammation (e.g. S100B, GFAP, iNOS) in Hip homogenates was found. On the contrary, data from 12 months old mice revealed a reduction of some of these factors, suggesting a decrease of glia activity. Conclusions - Our data indicate that PEA treatment affects brain metabolism. The current investigation provides evidence that PEA rescues altered molecular pathways that can mimic some traits of AD. Considering the safety and tolerability of PEA in humans, our findings offer new opportunity in AD treatment