Short-Term Memory Deficit Associates with miR-153-3p Upregulation in the Hippocampus of Middle-Aged Mice.

The early stages of ageing are a critical time window in which the ability to detect and identify precocious molecular and cognitive markers can make the difference in determining a healthy vs unhealthy course of ageing. Using the 6-different object task (6-DOT), a highly demanding hippocampal-dependent recognition memory task, we classified a population of middle-aged (12-month-old) CD1 male mice in Impaired and Unimpaired based on their short-term memory. This approach led us to identify a different microRNAs expression profile in the hippocampus of Impaired mice compared to Unimpaired ones. Among the dysregulated microRNAs, miR-153-3p was upregulated in the hippocampus of Impaired mice and appeared of high interest for its putative target genes and their possible implication in memory-related synaptic plasticity. We showed that intra-hippocampal injection of the miR-153-3p mimic in adult (3-month-old) mice is sufficient to induce a short-term memory deficit similar to that observed in middle-aged Impaired mice. Overall, these findings unravel a novel role for hippocampal miR-153-3p in modulating short-term memory that could be exploited to prevent early cognitive deficits in ageing.

Transcriptomic response in thermally challenged seahorses Hippocampus erectus: The effect of magnitude and rate of temperature change.

Hippocampus erectus inhabiting the shallow coastal waters of the southern Gulf of Mexico are naturally exposed to marked temperature variations occurring in different temporal scales. Under such heterogeneous conditions, a series of physiological and biochemical adjustments take place to restore and maintain homeostasis. This study investigated the molecular mechanisms involved in the response of H. erectus to increased temperature using transcriptome analysis based on RNA-Seq technology. Data was obtained from seahorses after 0.5-h exposure to combinations of different target temperatures (26 °C: control, and increased to 30 and 33 °C) and rates of thermal increase (abrupt: < 5 min; gradual: 1-1.5 °C every 3 h). The transcriptome of seahorses was assembled de novo using Trinity software to obtain 29,211 genes and 30,479 transcripts comprising 27,520,965 assembled bases. Seahorse exposure to both 30 and 33 °C triggered characteristic processes of the cellular stress response, regardless of the rate of thermal change. The transcriptomic profiles of H. erectus suggest an arrest of muscle development processes, the activation of heat shock proteins, and a switch to anaerobic metabolism within the first 0.5 h of exposure to target temperatures to ensure energy supply. Interestingly, apoptotic processes involving caspase were activated principally in gradual treatments, suggesting that prolonged exposure to even sublethal temperatures results in the accumulation of deleterious effects that may eventually terminate in cellular death. Results herein validate 30 °C and 33 °C as potential upper limits of thermal tolerance for H. erectus at the southernmost boundary of its geographic distribution.

TwinLiverNet: Predicting TACE Treatment Outcome from CT scans for Hepatocellular Carcinoma using Deep Capsule Networks.

Predicting response to treatment plays a key role to assist radiologists in hepato-cellular carcinoma (HCC) therapy planning. The most widely used treatment for unresectable HCC is the trans-arterial chemoembolization (TACE). A complete radiological response after the first TACE is a reliable predictor of treatment favourable outcome. However, visual inspection of contrast-enhanced CT scans is time-consuming, error prone and too operator-dependent. Thus, in this paper we propose TwinLiverNet: a deep neural network that is able to predict TACE treatment outcome through learning visual cue from CT scans. TwinLiverNet, specifically, integrates 3D convolutions and capsule networks and is designed to process simultaneously late arterial and delayed phases from contrast-enhanced CTs. Experimental results carried out on a dataset consisting of 126 HCC lesions show that TwinLiverNet reaches an average accuracy of 82% in predicting complete response to TACE treatment. Furthermore, combining multiple CT phases (specifically, late arterial and delayed ones) yields a performance increase of over 12 percent points. Finally, the introduction of capsule layers into the model avoids the model to overfit, while enhancing accuracy.Clinical relevance- TwinLiverNet supports radiologists in visual inspection of CT scans to assess TACE treatment outcome, while reducing inter-operator variability.

Metabolic syndrome in the era of COVID-19 outbreak: impact of lockdown on cardiometabolic health.

PURPOSE: COVID-19 pandemics and cardiometabolic health are mutually interconnected. Chronic metabolic diseases are known risk factors for increased mortality after SARS-CoV-2 infection. In turn, COVID pandemics imposed sudden changes in lifestyle and social isolation with consequent potential cardiometabolic sequelae. The present study aimed at investigating the impact of changes in lifestyle and social life on metabolic profile in hyperprolactinemic or osteoporotic patients without pre-existing cardiometabolic diseases at the time of COVID-19. METHODS: The primary study outcome measurement was the prevalence of obesity, arterial hypertension, impaired glucose tolerance (IGT) or diabetes mellitus (DM), dyslipidemia and metabolic syndrome after COVID-19 outbreak. Seventy-four patients (21 men and 53 women, aged 51.8 ± 17.8 years) were admitted to the outpatient clinic of the Neuroendocrine Disease Unit at University "Federico II" of Naples, Italy, as per their routine clinical practice because of tumoral and non-tumoral hyperprolactinemia in 52 patients (70.3%), and osteoporosis/osteopenia in 22 (29.7%). Among female patients, 25 (47.2%) were at menopausal age. RESULTS: At the end of lockdown, prevalence of obesity (from 37.8% to 51.3%, p < 0.0001), dyslipidemia (from 28.4 to 48.6%, p = 0.003) and metabolic syndrome (from 14.9 to 27%, p < 0.0001) significantly increased compared to pre-COVID evaluation. No significant change was found in the prevalence of arterial hypertension and IGT/DM. CONCLUSION: SARS-CoV-2 outbreak has led to a rapid increase in the prevalence of metabolic syndrome, potentially contributing to the increased COVID-19 related mortality.

Dermatofibrosarcoma protuberans: a tumor in the wide spectrum of the bland-looking spindle cell lesions of the breast.

Dermatofibrosarcoma protuberans (DFSP) is a soft tissue tumor, usually occurring as a cutaneous lesion localized to the trunk or extremities; although it has a high rate of local recurrence, its metastatic potential is very low and complete surgical excision is frequently curative. Most of the cases reported as "DFSP of the breast" are tumors arising in the subcutaneous tissue infiltrating the underlying breast parenchyma. To the best of our knowledge, only 5 cases of DFSP of the breast have been reported to date. We herein present a rare case of DFSP of the breast parenchyma in a 41-year-old female with emphasis on the diagnostic clues and the differential diagnosis with other benign and malignant spindle cell lesions of the breast.

Practical approach to diagnosis of bland-looking spindle cell lesions of the breast.

The diagnosis of bland-looking spindle cell lesions of the breast is often challenging because there is a close morphological and immunohistochemical overlap among the different entities. The present review will discuss reactive spindle cell nodule/exuberant scar, nodular fasciitis, inflammatory pseudotumor, myofibroblastoma (classic type), lipomatous myofibroblastoma, palisaded myofibroblastoma, benign fibroblastic spindle cell tumor, spindle cell lipoma, fibroma, leiomyoma, solitary fibrous tumor, myxoma, schwannoma/neurofibroma, desmoid-type fibromatosis, dermatofibrosarcoma protuberans, low-grade fibromatosis-like spindle cell carcinoma, inflammatory myofibroblastic tumor and low-grade myofibroblastic sarcoma arising in the breast parenchyma. The pathologist should be aware of each single lesion to achieve a correct diagnosis to ensure patient a correct prognostic information and therapy. Accordingly representative illustrations and morphological/immunohistochemical diagnostic clues will be provided.

Intestinal-type adenocarcinoma of the vagina: clinico-pathologic features of a common tumor with a rare localization.

Intestinal-type adenocarcinoma is a rare primary vaginal carcinoma and considerably more uncommon than metastatic lesions which represent the most frequent malignancy at this anatomic site. Among all malignant tumors, colorectal, breast and female genital tract carcinomas have the tendency to metastasize to the vagina.As morphologic and immunohistochemical features of intestinal-type adenocarcinoma occurring primarily in the vagina are not specific, clinical and radiologic information is crucial to exclude a metastatic lesion.Herein we present a rare case of intestinal-type adenocarcinoma from a villous adenoma, presenting as a polypoid mass in the posterior wall of vaginal introitus of 51-year-old menopausal woman. To the best of our knowledge, only 19 cases of intestinal-type adenocarcinoma of the vagina have been reported in the English literature so far. Notably the origin from a previous villous adenoma has been well documented only in a few cases.

Calcifying aponeurotic fibroma: a core biopsy-based diagnosis.

Calcifying aponeurotic fibroma (CAF) is a very rare tumor of the extremities, which can be difficult to diagnose due to its wide cyto-architectural pattern. We herein report the clinicopathologic features of a case of CAF localized on the dorsal face of the foot in a 5-year-old male child, diagnosed by needle core biopsy. Differential diagnostic problems are discussed. The present case emphasizes that the diagnosis of CAF can be confidentially rendered on core needle biopsy if the main morphological components of this tumor are concurrently present; however, before making the diagnosis of CAF, the clinical and radiological context should be considered.

A nontoxic pain killer designed by modeling of pathological receptor conformations.

Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathological (rather than physiological) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral µ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro. It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential.

MicroRNA-335-5p modulates spatial memory and hippocampal synaptic plasticity.

MicroRNAs are endogenous, noncoding RNAs crucial for the post-transcriptional regulation of gene expression. In this study, we investigated the role of miR-335-5p in spatial learning and synaptic plasticity. To this end we first showed spatial learning induced down-regulation of miR-335-5p. Next we found impairment in long-term memory and reduction in hippocampal long-term potentiation by exogenous administration of the miRNA. These findings demonstrate that miR-335-5p is a key coordinator of the intracellular pathways that mediate experience-dependent changes in the brain.

Lipomatous myofibroblastoma of the breast: case report with diagnostic and histogenetic considerations.

We report rare case of myofibroblastoma (MFB) of the breast comprised predominantly of a mature fatty component, representing approximately 70% of the entire tumour area. This tumour, designated "lipomatous MFB", should be interpreted as the morphological result of an unbalanced bidirectional differentiation of the precursor mammary stromal cell, with the adipocytic component overwhelming the fibroblastic/myofibroblastic one. Lipomatous MFB is a rare variant of mammary MFB, which can mimic malignancy because of the close juxtaposition of fibroblasts/myofibroblasts with mature adipocytes, resulting in a finger-like infiltrative growth pattern of the former towards the latter. Histogenetic considerations and differential diagnostic problems with other bland-looking spindle cell tumours containing infiltrating fat are provided.

Lipomatous angiomyofibroblastoma of the vulva: diagnostic and histogenetic considerations.

We report a rare case of angiomyofibroblastoma (AMFB) of the vulva, composed predominantly of a mature fatty component, representing approximately 60% of the entire tumour. The tumour, designated as "lipomatous AMFB", should be interpreted as the morphological result of an unbalanced bidirectional differentiation of the presumptive precursor stromal cell resident in the hormonally-responsive stroma of the lower genital tract, with the adipocytic component overwhelming the fibroblastic/myofibroblastic one. The close admixture of adipocytes with spindled/epithelioid cells of the conventional AMFB resulted, focally, in a pseudo-infiltrative growth pattern and pseudo-lipoblast-like appearance, raising problems in differential diagnosis, especially with well-differentiated lipoma-like liposarcoma and spindle cell liposarcoma. Awareness of the possibility that vulvo-vaginal AMFB may contain large amount of lipomatous component is crucial to avoid confusion with other bland-looking spindle cell tumours containing infiltrating fat.

Primary neuroendocrine lung tumor presenting with acute ileal obstruction. Case report.

The authors describe a clinical case of a patient with neuroendocrine carcinoma of the lung diagnosed after the onset of an intestinal obstruction from an ileal metastasis. A review of literature reveals that the incidence of symptomatic gastro-intestinal metastases from lung cancer has been estimated to be about 2-3% and is exceedingly rare that the intestinal symptoms may be the initial presentation of cancer of the lung. The authors emphasize the difficulty of preoperative diagnosis of gastro-intestinal metastases which is made, almost always, too late because of the lack of specific symptoms. In our case, on account of the computed tomography, we leaned towards the diagnosis of lymphoma because of the double mediastinal and abdominal localization. Furthermore, this diagnosis was supported by the fact that the pulmonary lesion did not have clear radiological features of a lung cancer. The prognosis is poor because once intestinal metastases occur, other metastatic sites, which would make surgery only a palliative measure, are already present. The review of the literature shows that the average survival rate of these patients is 136 days. In our case the patient survived 277 days.

Intraparenchymal leiomyoma of the breast: report of a case with emphasis on needle core biopsy-based diagnosis.

OBJECTIVE: We report the clinicopathologic features of a rare case of leiomyoma of the breast parenchyma in a 36-year-old female, diagnosed preoperatively at core biopsy. A complete review of the literature on the topic is provided and differential diagnostic problems are discussed. METHODS: Standard histological examination and immunohistochemical analyses using a large panel of antibodies were performed in both the core biopsy and surgical specimen. RESULTS: Ultrasonography revealed a well-circumscribed tumour mass without calcifications. Histological examination of the core biopsy showed proliferation of bland-looking eosinophilic spindle cells arranged in a fascicular growth pattern. Mitoses, pleomorphism and necrosis were absent. Immunohistochemistry, revealing diffuse staining for a-smooth muscle actin, desmin and h-caldesmon, confirmed the leiomiomatous nature of neoplastic cells. Histological and immunohistochemical analyses of the surgical specimen confirmed the definitive diagnosis of leiomyoma. CONCLUSIONS: The present case emphasizes that diagnosis of leiomyoma of the breast parenchyma can be confidentially rendered on needle core biopsy. We believe that correct diagnosis is primarily dependent on the awareness that this tumour can arise in this unusual site on rare occasions.

In vivo assessment of CdSe-ZnS quantum dots: coating dependent bioaccumulation and genotoxicity.

Semiconductor nanocrystals, or Quantum Dots (QDs), have gained considerable attention due to their unique size-dependent optical and electronic properties that make them attractive for a wide range of applications, including biology and nanomedicine. Their widespread use, however, poses urgent questions about their potential toxicity, especially because of their heavy metal composition that could cause harmful effects to human health and environment. In this work, we evaluated in vivo the long-term toxicity of CdSe-ZnS QDs with different surface coatings, probing oral administration in the model system Drosophila melanogaster. In particular, we found that all the differently coated QDs significantly affect the lifespan of treated Drosophila populations and induce a marked increase in reactive oxygen species (ROS) levels. Furthermore, we observed that these QDs induce severe genotoxic effects and increased rate of apoptosis in Drosophila haemocytes. These toxic effects were found to be mainly related to the in vivo degradation of QDs with consequent release of Cd(2+) ions, while the coating of QDs can modulate their bioaccumulation in the organism, partly decreasing their overall toxicity.

Sodium caprate transiently opens claudin-5-containing barriers at tight junctions of epithelial and endothelial cells.

Claudin-5 is a tight junction (TJ) protein which limits the diffusion of small hydrophilic molecules. Thus, it represents a potential pharmacological target to improve drug delivery to the tissues protected by claudin-5-dependent barriers. Sodium caprate is known as an absorption enhancer which opens the paracellular space acting on TJ proteins and actin cytoskeleton. Its action on claudin-5 is not understood so far. Epithelial and endothelial systems were used to evaluate the effect of caprate on claudin-5 in TJ-free cells and on claudin-5 fully integrated in TJ. To this aim, confocal microscopy on live and fixed cells and isolated mouse brain capillaries, Western blotting and permeability assays were employed. Caprate reversibly reduced claudin-5 trans-interactions in TJ-free human embryonic kidney-293 cells expressing claudin-5-YFP. It decreased the membranous claudin-5 and the F-actin content in Madin-Darby canine kidney-II cells expressing Flag-claudin-5, thereby increasing the permeability to the small molecule lucifer yellow. Interestingly, zonula occludens protein 1 (ZO-1), which links transmembranous TJ proteins to the actin cytoskeleton, was not affected by caprate treatment. Similarly, endogenous claudin-5 in the membrane of brain endothelia was displaced together with F-actin, whereas ZO-1 remained unaffected. Caprate transiently opens the paracellular space, reducing the intercellular claudin-5/claudin-5 interactions and the polymerized actin at the perijunctional region of endothelial and epithelial cells. In conclusion, the study further elucidates the cellular effects of caprate at the tight junctions.

Isolation of rat embryonic stem-like cells: a tool for stem cell research and drug discovery.

The establishment of rat embryonic stem cells constitutes a precious tool since rat has been extensively used in biomedical research, in particular for the generation of human neurodisease animal models. Up to now only a few studies have described the isolation of rat embryonic stem-like cells. One out of 9 isolated rat embryonic stem-like cell lines (B1-RESC) obtained from a 4.5-day post-coitum blastocyst were extensively characterized and kept in culture for up to 80 passages on feeders with LIF. The stable growth of these cells and the expression of pluripotent markers were confirmed up to a high number of passages in culture, also in the absence of feeders and LIF. B1-RESC expresses the three germ layers markers both in vitro, within differentiating embryoid bodies, and in vivo through teratoma formation. Collectively, the B1-RESC line with a stable near-diploid karyotype can be used as a highly sensitive tool for testing anti-proliferative molecules.

Triiodothyronine administration ameliorates the demyelination/remyelination ratio in a non-human primate model of multiple sclerosis by correcting tissue hypothyroidism.

Remyelination failure is a key landmark in chronic progression of multiple sclerosis (MS), the most diffuse demyelinating disease in human, but the reasons for this are still unknown. It has been shown that thyroid hormone administration in the rodent models of acute and chronic demyelinating diseases improved their clinical course, pathology and remyelination. In the present study, we translated this therapeutic attempt to experimental allergic encephalomyelitis (EAE) in the non-human primate Callithrix Jacchus (marmoset). We report that short protocols of triiodothyronine treatment shifts the demyelination/remyelination balance toward remyelination, as assessed by morphology, immunohistochemistry and molecular biology, and improves the clinical course of the disease. We also found that severely ill animals display hypothyroidism and severe alteration of deiodinase and thyroid hormone receptor mRNAs expression in the spinal cord, which was completely corrected by thyroid hormone treatment. We therefore suggest that thyroid hormone treatment improves myelin sheath morphology in marmoset EAE, by correcting the dysfunction of thyroid hormone cellular effectors.

Magnetic resonance imaging screening of cerebral thromboembolic events in children with acute lymphoblastic leukemia: a pilot study.

BACKGROUND: Thromboembolism is a complication of acute lymphoblastic leukemia therapy in children. The majority of thromboembolic events are cerebral thromboses and deep venous thromboses; many asymptomatic deep venous thromboses are detected in children with acute lymphoblastic leukemia by instrumental screening. The aim of this study was to assess the incidence of asymptomatic cerebral thromboembolic events in children with acute lymphoblastic leukemia (ALL) screened by magnetic resonance imaging and magnetic resonance venography. METHODS: 46 children with acute lymphoblastic leukemia, during the induction phase of the AIEOP ALL 2000 protocol, were stratified into 2 groups. In group "A" cerebral thromboembolic events were suspected following the appearance of suggestive signs and symptoms and confirmed by cerebral magnetic resonance imaging and magnetic resonance venography; in group "B" children underwent a screening by cerebral magnetic resonance imaging and magnetic resonance venography, at set times, in absence of symptoms. RESULTS: We observed one cerebral thromboembolic event in both groups; we found no differences between early detecting asymptomatic cerebral thromboembolic events among monitored and not monitored patients. CONCLUSIONS: Our study does not seem to suggest a screening for asymptomatic cerebral thromboembolic events in children with ALL during the induction phase.

Physical assessment of toxicology at nanoscale: nano dose-metrics and toxicity factor.

In this work, we propose a systematic and reproducible evaluation of nanoparticles (NPs) toxicology in living systems, based on a physical assessment and quantification of the toxic effects of NPs by the experimental determination of the key parameter affecting the toxicity outcome (i.e., the number of NPs) and of the NPs "toxicity factor". Such a strategy was applied to a well determined scenario, i.e., the ingestion of citrate-capped gold NPs (AuNPs) of different sizes by the model system Drosophila melanogaster. Using these AuNPs as a reference toxicity standard, we were able to define different regions in the multiparametric space of toxicity, enabling the classification of the toxic levels of other nanomaterials, such as quantum dots and pegylated AuNPs. This approach may pave the way to a systematic classification of nanomaterials, leading to important developments in risk assessment and regulatory approval, as well as in a wide range of nanomedicine applications.