Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) Significantly Improve Prostate Cancer Detection at Initial Biopsy in a Total PSA Range of 2-10 ng/ml

Many efforts to reduce prostate specific antigen (PSA) overdiagnosis and overtreatment have been made. To this aim, Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) have been proposed as new more specific biomarkers. We evaluated the ability of phi and PCA3 to identify prostate cancer (PCa) at initial prostate biopsy in men with total PSA range of 2-10 ng/ml. The performance of phi and PCA3 were evaluated in 300 patients undergoing first prostate biopsy. ROC curve analyses tested the accuracy (AUC) of phi and PCA3 in predicting PCa. Decision curve analyses (DCA) were used to compare the clinical benefit of the two biomarkers. We found that the AUC value of phi (0.77) was comparable to those of %p2PSA (0.76) and PCA3 (0.73) with no significant differences in pairwise comparison (%p2PSA vs phi p = 0.673, %p2PSA vs. PCA3 p = 0.417 and phi vs. PCA3 p = 0.247). These three biomarkers significantly outperformed fPSA (AUC = 0.60), %fPSA (AUC = 0.62) and p2PSA (AUC = 0.63). At DCA, phi and PCA3 exhibited a very close net benefit profile until the threshold probability of 25%, then phi index showed higher net benefit than PCA3. Multivariable analysis showed that the addition of phi and PCA3 to the base multivariable model (age, PSA, %fPSA, DRE, prostate volume) increased predictive accuracy, whereas no model improved single biomarker performance. Finally we showed that subjects with active surveillance (AS) compatible cancer had significantly lower phi and PCA3 values (p < 0.001 and p = 0.01, respectively). In conclusion, both phi and PCA3 comparably increase the accuracy in predicting the presence of PCa in total PSA range 2-10 ng/ml at initial biopsy, outperforming currently used %fPSA

Adenoviral gene transfer of PLD1-D4 enhances insulin sensitivity in mice by disrupting phospholipase D1 interaction with PED/PEA-15.

Over-expression of phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) causes insulin resistance by interacting with the D4 domain of phospholipase D1 (PLD1). Indeed, the disruption of this association restores insulin sensitivity in cultured cells over-expressing PED/PEA-15. Whether the displacement of PLD1 from PED/PEA-15 improves insulin sensitivity in vivo has not been explored yet. In this work we show that treatment with a recombinant adenoviral vector containing the human D4 cDNA (Ad-D4) restores normal glucose homeostasis in transgenic mice overexpressing PED/PEA-15 (Tg ped/pea-15) by improving both insulin sensitivity and secretion. In skeletal muscle of these mice, D4 over-expression inhibited PED/PEA-15-PLD1 interaction, decreased Protein Kinase C alpha activation and restored insulin induced Protein Kinase C zeta activation, leading to amelioration of insulin-dependent glucose uptake. Interestingly, Ad-D4 administration improved insulin sensitivity also in high-fat diet treated obese C57Bl/6 mice. We conclude that PED/PEA-15-PLD1 interaction may represent a novel target for interventions aiming at improving glucose tolerance

Serotoninergic receptor ligands improve Tamoxifen effectiveness on breast cancer cells

Background: Serotonin (or 5-Hydroxytryptamine, 5-HT) signals in mammary gland becomes dysregulated in cancer, also contributing to proliferation, metastasis, and angiogenesis. Thus, the discovery of novel compounds targeting serotonin signaling may contribute to tailor new therapeutic strategies usable in combination with endocrine therapies. We have previously synthesized serotoninergic receptor ligands (SER) with high affinity and selectivity towards 5-HT2A and 5-HT2C receptors, the main mediators of mitogenic effect of serotonin in breast cancer (BC). Here, we investigated the effect of 10 SER on viability of MCF7, SKBR3 and MDA-MB231 BC cells and focused on their potential ability to affect Tamoxifen responsiveness in ER+ cells. Methods: Cell viability has been assessed by sulforhodamine B assay. Cell cycle has been analyzed by flow cytometry. Gene expression of 5-HT receptors and Connective Tissue Growth Factor (CTGF) has been checked by RT-PCR; mRNA levels of CTGF and ABC transporters have been further measured by qPCR. Protein levels of 5-HT2C receptors have been analyzed by Western blot. All data were statistically analyzed using GraphPad Prism 7. Results: We found that treatment with SER for 72 h reduced viability of BC cells. SER were more effective on MCF7 ER+ cells (IC50 range 10.2 μM - 99.2 μM) compared to SKBR3 (IC50 range 43.3 μM - 260 μM) and MDA-MB231 BC cells (IC50 range 91.3 μM - 306 μM). This was paralleled by accumulation of cells in G0/G1 phase of cell cycle. Next, we provided evidence that two ligands, SER79 and SER68, improved the effectiveness of Tamoxifen treatment in MCF7 cells and modulated the expression of CTGF, without affecting viability of MCF10A non-cancer breast epithelial cells. In a cell model of Tamoxifen resistance, SER68 also restored drug effect independently of CTGF. Conclusions: These results identified serotoninergic receptor ligands potentially usable in combination with Tamoxifen to improve its effectiveness on ER+ BC patients

Diurnal variations of resting-state fMRI data : a graph-based analysis

Circadian rhythms (lasting approximately 24 h) control and entrain various physiological processes, ranging from neural activity and hormone secretion to sleep cycles and eating habits. Several studies have shown that time of day (TOD) is associated with human cognition and brain functions. In this study, utilizing a chronotype-based paradigm, we applied a graph theory approach on resting-state functional MRI (rs-fMRI) data to compare whole-brain functional network topology between morning and evening sessions and between morning-type (MT) and evening-type (ET) participants. Sixty-two individuals (31 MT and 31 ET) underwent two fMRI sessions, approximately 1 hour (morning) and 10 h (evening) after their wake-up time, according to their declared habitual sleep-wake pattern on a regular working day. In the global analysis, the findings revealed the effect of TOD on functional connectivity (FC) patterns, including increased small-worldness, assortativity, and synchronization across the day. However, we identified no significant differences based on chronotype categories. The study of the modular structure of the brain at mesoscale showed that functional networks tended to be more integrated with one another in the evening session than in the morning session. Local/regional changes were affected by both factors (i.e., TOD and chronotype), mostly in areas associated with somatomotor, attention, frontoparietal, and default networks. Furthermore, connectivity and hub analyses revealed that the somatomotor, ventral attention, and visual networks covered the most highly connected areas in the morning and evening sessions: the latter two were more active in the morning sessions, and the first was identified as being more active in the evening. Finally, we performed a correlation analysis to determine whether global and nodal measures were associated with subjective assessments across participants. Collectively, these findings contribute to an increased understanding of diurnal fluctuations in resting brain activity and highlight the role of TOD in future studies on brain function and the design of fMRI experiments

miR135a administration ameliorates brain ischemic damage by preventing TRPM7 activation during brain ischemia

Background: miRNA-based strategies have recently emerged as a promising therapeutic approach in several neurodegenerative diseases. Unregulated cation influx is implicated in several cellular mechanisms underlying neural cell death during ischemia. The brain constitutively active isoform of transient receptor potential melastatin 7 (TRPM7) represents a glutamate excitotoxicity-independent pathway that significantly contributes to the pathological Ca2+ overload during ischemia. Aims: In the light of these premises, inhibition of TRPM7 may be a reasonable strategy to reduce ischemic injury. Since TRPM7 is a putative target of miRNA135a, the aim of the present paper was to evaluate the role played by miRNA135a in cerebral ischemia. Therefore, the specific objectives of the present paper were: (1) to evaluate miR135a expression in temporoparietal cortex of ischemic rats; (2) to investigate the effect of the intracerebroventricular (icv) infusion of miR135a on ischemic damage and neurological functions; and (3) to verify whether miR135a effects may be mediated by an alteration of TRPM7 expression. Methods: miR135a expression was evaluated by RT- PCR and FISH assay in temporoparietal cortex of ischemic rats. Ischemic volume and neurological functions were determined in rats subjected to transient middle cerebral artery occlusion (tMCAo) after miR135a intracerebroventricular perfusion. Target analysis was performed by Western blot. Results: Our results demonstrated that, in brain cortex, 72 h after ischemia, miR135a expression increased, while TRPM7 expression was parallelly downregulated. Interestingly, miR135a icv perfusion strongly ameliorated the ischemic damage and improved neurological functions, and downregulated TRPM7 protein levels. Conclusions: The early prevention of TRPM7 activation is protective during brain ischemia

Epicardial Adipose Tissue and IL-13 Response to Myocardial Injury Drives Left Ventricular Remodeling After ST Elevation Myocardial Infarction

Introduction: Left ventricular (LV) remodeling after ST-segment elevation myocardial infarction (STEMI) is explained only in part by the infarct size, and the inter-patient variability may be ascribed to different inflammatory response to myocardial injury. Epicardial adipose tissue (EAT) is a source of inflammatory mediators which directly modulates the myocardium. EAT increase is associated to several cardiovascular diseases; however, its response to myocardial injury is currently unknown. Among inflammatory mediators, IL-13 seems to play protective role in LV regeneration, but its variations after STEMI have not been described yet. Purpose: In the present study we analyzed the association between infarct-related changes of EAT and IL-13 in post-STEMI LV remodeling. Methods: We enrolled 100 patients with STEMI undergoing primary angioplasty. At the enrolment (T0) and after 3 months (T1), we measured EAT thickness by echocardiography and circulating levels of IL-13 by ELISA. Results: At T1, the 60% of patients displayed increased EAT thickness (ΔEAT &gt; 0). ΔEAT was directly associated to LV end-diastolic volume (r = 0.42; p = 0.014), LV end-systolic volume (r = 0.42; p = 0.013) and worse LV ejection fraction (LVEF) at T1 (r = −0.44; p = 0.0094), independently of the infarct size. In the overall population IL-13 levels significantly decreased at T1 (p = 0.0002). The ΔIL-13 was directly associated to ΔLVEF (r = 0.42; p = 0.017) and inversely related to ΔEAT (r = −0.51; p = 0.022), thus suggesting a protective role for IL-13. Conclusion: The variability of STEMI-induced “inflammatory response” may be associated to the post-infarct LV remodeling. ΔEAT thickness and ΔIL-13 levels could be novel prognostic markers in STEMI patients

Novel USH1G homozygous variant underlying USH2-like phenotype of Usher syndrome

PURPOSE: Usher syndrome (USH) is an autosomal recessive disorder characterized by congenital sensorineural hearing impairment and retinitis pigmentosa. Classification distinguishes three clinical types of which type I (USH1) is the most severe, with vestibular dysfunction as an added feature. To date, 15 genes and 3 loci have been identified with the USH1G gene being an uncommon cause of USH. We describe an atypical USH1G-related phenotype caused by a novel homozygous missense variation in a patient with profound hearing impairment and relatively mild retinitis pigmentosa, but no vestibular dysfunction. METHODS: A 26-year-old female patient with profound congenital sensorineural hearing loss, nyctalopia and retinitis pigmentosa was studied. Audiometric, vestibular and ophthalmologic examination was performed. A panel of 13 genes was tested by next-generation sequencing (NGS). RESULTS: While the hearing loss was confirmed to be profound, the vestibular function resulted normal. Although typical retinitis pigmentosa was present, the age at onset was unusually late for USH1 syndrome. A novel homozygous missense variation (c.1187T>A, p.Leu396Gln) in the USH1G gene has been identified as causing the disease in our patient. CONCLUSIONS: Genetic and phenotypic heterogeneity are very common in both isolated and syndromic retinal dystrophies and sensorineural hearing loss. Our findings widen the spectrum of USH allelic disorders and strength the concept that variants in genes that are classically known as underlying one specific clinical USH subtype might result in unexpected phenotypes

Human Platelet-Rich Plasma Regulates Canine Mesenchymal Stem Cell Migration through Aquaporins

Platelet products are commonly used in regenerative medicine due to their effects on the acceleration and promotion of wound healing, reduction of bleeding, synthesis of new connective tissue, and revascularization. Furthermore, a novel approach for the treatment of damaged tissues, following trauma or other pathological damages, is represented by the use of mesenchymal stem cells (MSCs). In dogs, both platelet-rich plasma (PRP) and MSCs have been suggested to be promising options for subacute skin wounds. However, the collection of canine PRP is not always feasible. In this study, we investigated the effect of human PRP (hPRP) on canine MSCs (cMSCs). We isolated cMSCs and observed that hPRP did not modify the expression levels of the primary class of major histocompatibility complex genes. However, hPRP was able to increase cMSC viability and migration by at least 1.5-fold. hPRP treatment enhanced both Aquaporin (AQP) 1 and AQP5 protein levels, and their inhibition by tetraethylammonium chloride led to a reduction of PRP-induced migration of cMSCs. In conclusion, we have provided evidence that hPRP supports cMSC survival and may promote cell migration, at least through AQP activation. Thus, hPRP may be useful in canine tissue regeneration and repair, placing as a promising tool for veterinary therapeutic approaches

Pain neuroimaging in humans: a primer for beginners and non-imagers

The field of human pain neuroimaging has exploded in the last two decades. During this time, the broader neuroimaging community has continued to investigate and refine methods. Another key to progress is exchange with clinicians and pain scientists working with other model systems and approaches. These collaborative efforts require that non-imagers be able to evaluate and assess the evidence provided in these papers. Likewise, new trainees must design rigorous and reliable pain imaging experiments. Here, we provide a guideline for designing, reading, evaluating, analyzing, and reporting results of a pain neuroimaging experiment, with a focus on functional and structural MRI. We focus in particular on considerations that are unique to neuroimaging studies of pain in humans, including study design and analysis, inferences that can be drawn from these studies, and the strengths and limitations of the approach. This article provides an overview of the concepts and considerations of structural and functional MRI neuroimaging studies. The primer is written for those who are not familiar with brain imaging. We review key concepts related to recruitment and study sample, experimental design, data analysis and data interpretation. [Abstract copyright: Copyright © 2018. Published by Elsevier Inc.

Platelet-rich plasma counteracts detrimental effect of high-glucose concentrations on mesenchymal stem cells from Bichat fat pad

Diabetic patients display increased risk of periodontitis and failure in bone augmentation procedures. Mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) represent a relevant advantage in tissue repair process and regenerative medicine. We isolated MSCs from Bichat's buccal fat pad (BFP) and measured the effects of glucose and PRP on cell number and osteogenic differentiation potential. Cells were cultured in the presence of 5.5-mM glucose (low glucose [LG]) or 25-mM glucose (high glucose [HG]). BFP–MSC number was significantly lower when cells were cultured in HG compared with those in LG. Following osteogenic differentiation procedures, calcium accumulation, alkaline phosphatase activity, and expression of osteogenic markers were significantly lower in HG compared with LG. Exposure of BFP–MSC to PRP significantly increased cell number and osteogenic differentiation potential, reaching comparable levels in LG and in HG. Thus, high-glucose concentrations impair BFP–MSC growth and osteogenic differentiation. However, these detrimental effects are largely counteracted by PRP