Post-Treated Prostate Cancer: Normal Findings and Signs of Local Relapse on Multiparametric Magnetic Resonance Imaging

The use of multiparametric magnetic resonance imaging (mp-MRI) for prostate cancer has increased over recent years, mainly for detection, staging, and active surveillance. However, suspicion of recurrence in the set of biochemical failure is becoming a significant reason for clinicians to request mp-MRI. Radiologists should be able to recognize the normal post-treatment MRI findings. Fibrosis and atrophic remnant seminal vesicles after prostatectomy are often found and must be differentiated from local relapse. Moreover, brachytherapy, external beam radiotherapy, cryosurgery, and hormonal therapy tend to diffusely decrease the signal intensity of the peripheral zone on T2-weighted images (T2WI) due to the loss of water content, consequently mimicking tumor and hemorrhage. The combination of T2WI and functional studies like diffusion-weighted imaging and dynamic contrast-enhanced improves the identification of local relapse. Tumor recurrence tends to restrict on diffusion images and avidly enhances after contrast administration either within or outside the gland. The authors provide a pictorial review of the normal findings and the signs of local tumor relapse after radical prostatectomy, external beam radiotherapy, brachytherapy, cryosurgery, and hormonal therapy

Cancro da Próstata: O Papel da Ressonância Magnética Multiparamétrica

Multiparametric Magnetic Resonance Imaging has been increasingly used for detection, localization and staging of prostate cancer over the last years. It combines high-resolution T2 Weighted-Imaging and at least two functional techniques, which include Dynamic Contrast–Enhanced Magnetic Resonance Imaging, Diffusion-Weighted Imaging, and Magnetic Resonance Imaging Spectroscopy. Although the combined use of a pelvic phased-array and an Endorectal Coil is considered the state-of-the-art for Magnetic Resonance Imaging evaluation of prostate cancer, Endorectal Coil is only absolute mandatory for Magnetic Resonance Imaging Spectroscopy at 1.5 T. Sensitivity and specificity levels in cancer detection and localization have been improving with functional technique implementation, compared to T2 Weighted-Imaging alone. It has been particularly useful to evaluate patients with abnormal PSA and negative biopsy. Moreover, the information added by the functional techniques may correlate to cancer aggressiveness and therefore be useful to select patients for focal radiotherapy, prostate sparing surgery, focal ablative therapy and active surveillance. However, more studies are needed to compare the functional techniques and understand the advantages and disadvantages of each one. This article reviews the basic principles of prostatic mp-Magnetic Resonance Imaging, emphasizing its role on detection, staging and active surveillance of prostate cancer

Chronic stress targets adult neurogenesis preferentially in the suprapyramidal blade of the rat dorsal dentate gyrus

First Online: 29 August 2017The continuous generation of new neurons and glial cells in the adult hippocampal dentate gyrus (DG) represents an important form of adult neuroplasticity, involved in normal brain function and behavior but also associated with the etiopathogenesis and treatment of psychiatric disorders. Despite the large number of studies addressing cell genesis along the septotemporal axis, data on the anatomical gradients of cytogenesis along the DG transverse axis is scarce, especially after exposure to stress. As such, in this study we characterized both basal proliferation and survival of adult-born neural cells along the transverse axis of the rat dorsal DG, and after stress exposure. In basal conditions, both proliferating cells and newborn neurons and glial cells were preferentially located at the subgranular zone and suprapyramidal blade. Exposure to chronic stress induced an overall decrease in the generation of adult-born neural cells and, more specifically, produced a regional-specific decrease in the survival of adult-born neurons at the suprapyramidal blade. No particular region-specific alterations were observed on surviving adult-born glial cells. This work reveals, for the first time, a distinct survival profile of adult-born neural cells, neurons and glial cells, among the transverse axis of the DG, in both basal and stress conditions. Our results unveil that adult-born neurons are preferentially located in the suprapyramidal blade and suggest a regional-specific impact of chronic stress in this blade with potential repercussions for its functional significance.NDA, PP, AMP, ARMS, MM and LP received fellowships from the Portuguese Foundation for Science and Technology (FCT). This work was funded by FCT (IF/01079/2014). This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038.info:eu-repo/semantics/publishedVersio

Beyond new neurons in the adult hippocampus: imipramine acts as a pro-astrogliogenic factor and rescues cognitive impairments induced by stress exposure

Depression is a prevalent, socially burdensome disease. Different studies have demonstrated the important role of astrocytes in the pathophysiology of depression as modulators of neurotransmission and neurovascular coupling. This is evidenced by astrocyte impairments observed in brains of depressed patients and the appearance of depressive-like behaviors upon astrocytic dysfunctions in animal models. However, little is known about the importance of de novo generated astrocytes in the mammalian brain and in particular its possible involvement in the precipitation of depression and in the therapeutic actions of current antidepressants (ADs). Therefore, we studied the modulation of astrocytes and adult astrogliogenesis in the hippocampal dentate gyrus (DG) of rats exposed to an unpredictable chronic mild stress (uCMS) protocol, untreated and treated for two weeks with antidepressants—fluoxetine and imipramine. Our results show that adult astrogliogenesis in the DG is modulated by stress and imipramine. This study reveals that distinct classes of ADs impact differently in the astrogliogenic process, showing different cellular mechanisms relevant to the recovery from behavioral deficits induced by chronic stress exposure. As such, in addition to those resident, the newborn astrocytes in the hippocampal DG might also be promising therapeutic targets for future therapies in the neuropsychiatric field.ARMS: ELC, NDA, PP, AMP, JSC, MM, AJR, JFO, and L.P. received fellowships from the Portuguese Foundation for Science and Technology (FCT) (IF/00328/2015 to J.F.O.; 2020.02855.CEECIND to LP). This work was funded by FCT (IF/01079/2014, PTDC/MED-NEU/31417/2017 Grant to JFO), BIAL Foundation Grants (037/18 to J.F.O. and 427/14 to L.P.), “la Caixa” Foundation Health Research Grant (LCF/PR/HR21/52410024) and Nature Research Award for Driving Global Impact—2019 Brain Sciences (to L.P.). This was also co-funded by the Life and Health Sciences Research Institute (ICVS), and by FEDER, through the Competitiveness Internationalization Operational Program (POCI), and by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020. Moreover, this work has been funded by ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122; by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020; “la Caixa” Foundation (ID 100010434 to A.J.R.), under the agreement LCF/PR/HR20/52400020; and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 101003187 to A.J.R.)

Synthesis, biological evaluation, and molecular modeling of nitrile-containing compounds : exploring multiple activities as anti-Alzheimer agents

Funding: EC COST Actions D34 and CM1103 for Short-term Scientific Mission funding (EM, DS, MM); the School of Biology at the University of St. Andrews (EJS, RRR); the Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa (AN, ACJ, TR, MCC); FCT, the Portuguese Foundation for Science and Technology (Project PTDC/SAU-NEU/64151/2006 (MCC), and project grant (DS) Vega 2/0127/18 and the contract No. APVV-15-0455 of Slovak Research and Development Agency (MM).Based on the monoamine oxidase (MAO) inhibition properties of aminoheterocycles with a carbonitrile group we have carried out a systematic exploration to discover new classes of carbonitriles endowed with dual MAO and AChE inhibitory activities, and Aβ anti‐aggregating properties. Eighty‐three nitrile‐containing compounds, 13 of which are new, were synthesized and evaluated. in vitro screening revealed that 31 , a new compound, presented the best lead for trifunctional inhibition against MAO A (0.34 μM), MAO B (0.26 μM), and AChE (52 μM), while 32 exhibited a lead for selective MAO A (0.12 μM) inhibition coupled to AChE (48 μM) inhibition. Computational analysis revealed that the malononitrile group can find an advantageous position with the aromatic cleft and FAD of MAO A or MAO B. However, the total binding energy can be handicapped by an internal penalty caused by twisting of the ligand molecule and subsequent disruption of the conjugation ( 32 in MAO B compared to the conjugated 31 ). Conjugation is also important for AChE as well as the hydrophilic character of malononitrile that allows this group to be in close contact with the aqueous environment as seen for 83 . Although the effect of 31 and 32 against Aβ1–42, was very weak, the effect of 63 and 65 , and of the new compound 75 , indicated that these compounds were able to disaggregate Aβ1–42 fibrils. The most effective was 63 , a (phenylhydrazinylidene)propanedinitrile derivative that also inhibited MAO A (1.65 μM), making it a potential lead for Alzheimer's disease application.PostprintPeer reviewe

AP2γ controls adult hippocampal neurogenesis and modulates cognitive, but not anxiety or depressive-like behavior

Hippocampal neurogenesis has been proposed to participate in a myriad of behavioral responses, both in basal states and in the context of neuropsychiatric disorders. Here, we identify activating protein 2γ 3 (AP2γ 3, also known as Tcfap2c), originally described to regulate the generation of neurons in the developing cortex, as a modulator of adult hippocampal glutamatergic neurogenesis in mice. Specifically, AP2γ 3 is present in a sub-population of hippocampal transient amplifying progenitors. There, it is found to act as a positive regulator of the cell fate determinants Tbr2 and NeuroD, promoting proliferation and differentiation of new glutamatergic granular neurons. Conditional ablation of AP2γ 3 in the adult brain significantly reduced hippocampal neurogenesis and disrupted neural coherence between the ventral hippocampus and the medial prefrontal cortex. Furthermore, it resulted in the precipitation of multimodal cognitive deficits. This indicates that the sub-population of AP2γ 3-positive hippocampal progenitors may constitute an important cellular substrate for hippocampal-dependent cognitive functions. Concurrently, AP2γ 3 deletion produced significant impairments in contextual memory and reversal learning. More so, in a water maze reference memory task a delay in the transition to cognitive strategies relying on hippocampal function integrity was observed. Interestingly, anxiety- and d epressive-like behaviors were not significantly affected. Altogether, findings open new perspectives in understanding the role of specific sub-populations of newborn neurons in the (patho)physiology of neuropsychiatric disorders affecting hippocampal neuroplasticity and cognitive function in the adult brain.We acknowledge the excellent technical expertise of Luís Martins and Andrea Steiner-Mezzadri. We would also like to acknowledge Magdalena Götz for the insightful comments on the paper. AMP, PP, ARS, JS, VMS, NDA and JFO received fellowships from the Portuguese Foundation for Science and Technology (FCT). LP received fellowship from FCT and her work is funded by FCT (IF/01079/2014) and Bial Foundation (427/14) projects. This work was cofunded by the Life and Health Sciences Research Institute (ICVS), and Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (projects NORTE-01-0145- FEDER-000013 and NORTE-01-0145-FEDER-000023). This work has been also funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the FCT, under the scope of the project POCI-01-0145-FEDER-007038info:eu-repo/semantics/publishedVersio

The genetic landscape of mitochondrial diseases in the next-generation sequencing era: a Portuguese cohort study

Introduction: Rare disorders that are genetically and clinically heterogeneous, such as mitochondrial diseases (MDs), have a challenging diagnosis. Nuclear genes codify most proteins involved in mitochondrial biogenesis, despite all mitochondria having their own DNA. The development of next-generation sequencing (NGS) technologies has revolutionized the understanding of many genes involved in the pathogenesis of MDs. In this new genetic era, using the NGS approach, we aimed to identify the genetic etiology for a suspected MD in a cohort of 450 Portuguese patients.Methods: We examined 450 patients using a combined NGS strategy, starting with the analysis of a targeted mitochondrial panel of 213 nuclear genes, and then proceeding to analyze the whole mitochondrial DNA.Results and Discussion: In this study, we identified disease-related variants in 134 (30%) analyzed patients, 88 with nuclear DNA (nDNA) and 46 with mitochondrial DNA (mtDNA) variants, most of them being pediatric patients (66%), of which 77% were identified in nDNA and 23% in mtDNA. The molecular analysis of this cohort revealed 72 already described pathogenic and 20 novel, probably pathogenic, variants, as well as 62 variants of unknown significance. For this cohort of patients with suspected MDs, the use of a customized gene panel provided a molecular diagnosis in a timely and cost-effective manner. Patients who cannot be diagnosed after this initial approach will be further selected for whole-exome sequencing.Conclusion: As a national laboratory for the study and research of MDs, we demonstrated the power of NGS to achieve a molecular etiology, expanding the mutational spectrum and proposing accurate genetic counseling in this group of heterogeneous diseases without therapeutic options