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The importance of sports and the approval of the Dual Career regulation at the University of Rome "Tor Vergata" are highly significant topics for the well-being and personal development of students. In line with European and international policies, this initiative recognizes the specific needs of student-athletes by offering them tools and flexibility to excel in both sports and academics. However, monitoring student-athletes by Universities requires thorough investigations and the development of initiatives to promote students' adherence to sports practice. Therefore, our study aims to analyze the results of a survey administered to students enrolled at the University of Rome "Tor Vergata" during the academic years 2020/2021, 2021/2022, 2022/2023, and 2023/2024, investigating the effects of the introduction of the Dual Career regulation on the student population. Our preliminary results showed that the introduction of the Dual Career program was associated with a significant increase in the number of students practising sports over the academic years, with greater participation in the academic years 2022/2023 and 2023/2024. Noteworthy, the number of student-athletes who applied to the Dual Career program markedly increased in the last year, with the highest number of enrollments in the macroareas of Medicine and Surgery, Economy, and Engineering. Overall, the Dual Career regulation offers the possibility to plan the study path in a personalized way, dedicated academic support, and flexibility in deadlines, making the University of Rome "Tor Vergata" a model of integration between education and sportiness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Cariati, Bonanni, Onorati and Tancredi.)

Resolutive cures for spinal cord injuries (SCIs) are still lacking, due to the complex pathophysiology. One of the most promising regenerative approaches is based on stem cell transplantation to replace lost tissue and promote functional recovery. This approach should be further explored better in vitro and ex vivo for safety and efficacy before proceeding with more expensive and time-consuming animal testing. In this work, we show the establishment of a long-term platform based on mouse spinal cord (SC) organotypic slices transplanted with human neural stem cells to test cellular replacement therapies for SCIs. Standard SC organotypic cultures are maintained for around 2 or 3 weeks in vitro. Here, we describe an optimized protocol for long-term maintenance (≥30 days) for up to 90 days. The medium used for long-term culturing of SC slices was also optimized for transplanting neural stem cells into the organotypic model. Human SC-derived neuroepithelial stem (h-SC-NES) cells carrying a green fluorescent protein (GFP) reporter were transplanted into mouse SC slices. Thirty days after the transplant, cells still show GFP expression and a low apoptotic rate, suggesting that the optimized environment sustained their survival and integration inside the tissue. This protocol represents a robust reference for efficiently testing cell replacement therapies in the SC tissue. This platform will allow researchers to perform an ex vivo pre-screening of different cell transplantation therapies, helping them to choose the most appropriate strategy before proceeding with in vivo experiments.

Human cytomegalovirus (HCMV) is the viral leading cause of congenital defects in newborns worldwide. Many aspects of congenital CMV (cCMV) infection, which currently lacks a specific treatment, as well as the main determinants of neuropathogenesis in the developing brain during HCMV infection are unclear. In this study, we modeled HCMV infection at different stages of neural development. Moreover, we evaluated the effects of both approved and investigational anti-HCMV drugs on viral replication and gene expression in two different neural progenitor cell lines, i.e., human embryonic stem cells-derived neural stem cells (NSCs) and fetus-derived neuroepithelial stem (NES) cells. Ganciclovir, letermovir, nitazoxanide, and the ozonide OZ418 reduced viral DNA synthesis and the production of infectious virus in both lines of neural progenitors. HCMV infection dysregulated the expression of genes that either are markers of neural progenitors, such as SOX2, NESTIN, PAX-6, or play a role in neurogenesis, such as Doublecortin. Treatment with antiviral drugs had different effects on HCMV-induced dysregulation of the genes under investigation. This study contributes to the understanding of the molecular mechanisms of cCMV neuropathogenesis and paves the way for further consideration of anti-HCMV drugs as candidate therapeutic agents for the amelioration of cCMV-associated neurological manifestations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Recent evidence suggests that lipids play a crucial role in viral infections beyond their traditional functions of supplying envelope and energy, and creating protected niches for viral replication. In the case of Zika virus (ZIKV), it alters host lipids by enhancing lipogenesis and suppressing β-oxidation to generate viral factories at the endoplasmic reticulum (ER) interface. This discovery prompted us to hypothesize that interference with lipogenesis could serve as a dual antiviral and anti-inflammatory strategy to combat the replication of positive sense single-stranded RNA (ssRNA+) viruses. To test this hypothesis, we examined the impact of inhibiting N-Acylethanolamine acid amidase (NAAA) on ZIKV-infected human Neural Stem Cells. NAAA is responsible for the hydrolysis of palmitoylethanolamide (PEA) in lysosomes and endolysosomes. Inhibition of NAAA results in PEA accumulation, which activates peroxisome proliferator-activated receptor-α (PPAR-α), directing β-oxidation and preventing inflammation. Our findings indicate that inhibiting NAAA through gene-editing or drugs moderately reduces ZIKV replication by approximately one log 10 in Human Neural Stem Cells, while also releasing immature virions that have lost their infectivity. This inhibition impairs furin-mediated prM cleavage, ultimately blocking ZIKV maturation. In summary, our study highlights NAAA as a host target for ZIKV infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Mechanical stimulation modulates neural development and neuronal activity. In a previous study, magnetic "nano-pulling" is proposed as a tool to generate active forces. By loading neural cells with magnetic nanoparticles (MNPs), a precise force vector is remotely generated through static magnetic fields. In the present study, human neural stem cells (NSCs) are subjected to a standard differentiation protocol, in the presence or absence of nano-pulling. Under mechanical stimulation, an increase in the length of the neural processes which showed an enrichment in microtubules, endoplasmic reticulum, and mitochondria is found. A stimulation lasting up to 82 days induces a strong remodeling at the level of synapse density and a re-organization of the neuronal network, halving the time required for the maturation of neural precursors into neurons. The MNP-loaded NSCs are then transplanted into mouse spinal cord organotypic slices, demonstrating that nano-pulling stimulates the elongation of the NSC processes and modulates their orientation even in an ex vivo model. Thus, it is shown that active mechanical stimuli can guide the outgrowth of NSCs transplanted into the spinal cord tissue. The findings suggest that mechanical forces play an important role in neuronal maturation which could be applied in regenerative medicine., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

WDR62 is a spindle pole-associated scaffold protein with pleiotropic functions. Recessive mutations in WDR62 cause structural brain abnormalities and account for the second most common cause of autosomal recessive primary microcephaly (MCPH), indicating WDR62 as a critical hub for human brain development. Here, we investigated WDR62 function in corticogenesis through the analysis of a C-terminal truncating mutation (D955AfsX112). Using induced Pluripotent Stem Cells (iPSCs) obtained from a patient and his unaffected parent, as well as isogenic corrected lines, we generated 2D and 3D models of human neurodevelopment, including neuroepithelial stem cells, cerebro-cortical progenitors, terminally differentiated neurons, and cerebral organoids. We report that WDR62 localizes to the Golgi apparatus during interphase in cultured cells and human fetal brain tissue, and translocates to the mitotic spindle poles in a microtubule-dependent manner. Moreover, we demonstrate that WDR62 dysfunction impairs mitotic progression and results in alterations of the neurogenic trajectories of iPSC neuroderivatives. In summary, impairment of WDR62 localization and function results in severe neurodevelopmental abnormalities, thus delineating new mechanisms in the etiology of MCPH., Competing Interests: CD, MA, YT, IS, MD, MG, EP, EC, AL, MO No competing interests declared, (© 2023, Dell'Amico et al.)

The human brain is the most complex structure generated during development. Unveiling the ontogenesis and the intrinsic organization of specific neural networks may represent a key to understanding the physio-pathological aspects of different brain areas. The cortico-thalamic and thalamo-cortical (CT-TC) circuits process and modulate essential tasks such as wakefulness, sleep and memory, and their alterations may result in neurodevelopmental and psychiatric disorders. These pathologies are reported to affect specific neural populations but may also broadly alter physiological connections and thus dysregulate brain network generation, communication, and function. More specifically, the CT-TC system is reported to be severely affected in disorders impacting superior brain functions, such as schizophrenia (SCZ), bipolar disorder, autism spectrum disorders or epilepsy. In this review, the focus will be on CT development, and the models exploited to uncover and comprehend its molecular and cellular mechanisms. In parallel to animal models, still fundamental to unveil human neural network establishment, advanced in vitro platforms, such as brain organoids derived from human pluripotent stem cells, will be discussed. Indeed, organoids and assembloids represent unique tools to study and accelerate fundamental research in CT development and its dysfunctions. We will then discuss recent cutting-edge contributions, including in silico approaches, concerning ontogenesis, specification, and function of the CT-TC circuitry that generates connectivity maps in physiological and pathological conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Angulo Salavarria, Dell’Amico, D’Agostino, Conti and Onorati.)

Congenital alterations in the levels of the transcription factor Forkhead box g1 (FOXG1) coding gene trigger "FOXG1 syndrome," a spectrum that recapitulates birth defects found in the "congenital Zika syndrome," such as microcephaly and other neurodevelopmental conditions. Here, we report that Zika virus (ZIKV) infection alters FOXG1 nuclear localization and causes its downregulation, thus impairing expression of genes involved in cell replication and apoptosis in several cell models, including human neural progenitor cells. Growth factors, such as EGF and FGF2, and Thr271 residue located in FOXG1 AKT domain, take part in the nuclear displacement and apoptosis protection, respectively. Finally, by progressive deletion of FOXG1 sequence, we identify the C-terminus and the residues 428-481 as critical domains. Collectively, our data suggest a causal mechanism by which ZIKV affects FOXG1, its target genes, cell cycle progression, and survival of human neural progenitors, thus contributing to microcephaly., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

As microtubule-organizing centers (MTOCs), centrosomes play a pivotal role in cell division, neurodevelopment and neuronal maturation. Among centrosomal proteins, centrin-2 (CETN2) also contributes to DNA repair mechanisms which are fundamental to prevent genomic instability during neural stem cell pool expansion. Nevertheless, the expression profile of CETN2 in human neural stem cells and their progeny is currently unknown. To address this question, we interrogated a platform of human neuroepithelial stem (NES) cells derived from post mortem developing brain or established from pluripotent cells and demonstrated that while CETN2 retains its centrosomal location in proliferating NES cells, its expression pattern changes upon differentiation. In particular, we found that CETN2 is selectively expressed in mature astrocytes with a broad cytoplasmic distribution. We then extended our findings on human autoptic nervous tissue samples. We investigated CETN2 distribution in diverse anatomical areas along the rostro-caudal neuraxis and pointed out a peculiar topography of CETN2-labeled astrocytes in humans which was not appreciable in murine tissues, where CETN2 was mostly confined to ependymal cells. As a prototypical condition with glial overproliferation, we also explored CETN2 expression in glioblastoma multiforme (GBM), reporting a focal concentration of CETN2 in neoplastic astrocytes. This study expands CETN2 localization beyond centrosomes and reveals a unique expression pattern that makes it eligible as a novel astrocytic molecular marker, thus opening new roads to glial biology and human neural conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Degl’Innocenti, Poloni, Medici, Recupero, Dell’Amico, Vannini, Borello, Mazzanti, Onorati and Dell’Anno.)

The growth of glioblastoma (GBM), one of the deadliest adult cancers, is fuelled by a subpopulation of stem/progenitor cells, which are thought to be the source of resistance and relapse after treatment. Re-engagement of a latent capacity of these cells to re-enter a trajectory resulting in cell differentiation is a potential new therapeutic approach for this devastating disease. ASCL1, a proneural transcription factor, plays a key role in normal brain development and is also expressed in a subset of GBM cells, but fails to engage a full differentiation programme in this context. Here, we investigated the barriers to ASCL1-driven differentiation in GBM stem cells. We see that ASCL1 is highly phosphorylated in GBM stem cells where its expression is compatible with cell proliferation. However, overexpression of a form of ASCL1 that cannot be phosphorylated on Serine-Proline sites drives GBM cells down a neuronal lineage and out of cell cycle more efficiently than its wild-type counterpart, an effect further enhanced by deletion of the inhibitor of differentiation ID2, indicating mechanisms to reverse the block to GBM cell differentiation., (© 2022. The Author(s).)

Snap29 is a conserved regulator of membrane fusion essential to complete autophagy and to support other cellular processes, including cell division. In humans, inactivating SNAP29 mutations causes CEDNIK syndrome, a rare multi-systemic disorder characterized by congenital neuro-cutaneous alterations. The fibroblasts of CEDNIK patients show alterations of the Golgi apparatus (GA). However, whether and how Snap29 acts at the GA is unclear. Here we investigate SNAP29 function at the GA and endoplasmic reticulum (ER). As part of the elongated structures in proximity to these membrane compartments, a pool of SNAP29 forms a complex with Syntaxin18, or with Syntaxin5, which we find is required to engage SEC22B-loaded vesicles. Consistent with this, in HeLa cells, in neuroepithelial stem cells, and in vivo , decreased SNAP29 activity alters GA architecture and reduces ER to GA trafficking. Our data reveal a new regulatory function of Snap29 in promoting secretory trafficking., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Morelli, Speranza, Pellegrino, Beznoussenko, Carminati, Garré, Mironov, Onorati and Vaccari.)

Histiocytic sarcoma (HS) is a rare malignant lymphohematopoietic neoplasm; it has been cited in the recent World Health Organization (WHO) classification as a malignant proliferation of cells exhibiting morphological and immunophenotypic features of mature histiocytes. To our knowledge, the present case is the first to be described in the bladder of a patient without a history of lymphoma. Only one case has been reported so far regarding a secondary bladder presentation in the setting of a previous diffuse large B-cell lymphoma. We discuss the case of a 68-year-old male who presented with hematuria and dysuria. CT scan revealed a 4-cm intravesical mass that histological examination defined as HS. Our objective was to describe the clinical, histological, immunophenotypical, molecular characteristics and discuss the differential diagnoses of this first case of primary bladder HS. Our research was based on a review of selected articles obtained via the PubMed database. This extremely rare experience provided us with the opportunity to depict an interesting case, highlight its uniqueness, and build up new pathological evidence., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Nicola et al.)

Introduction: Nowadays, endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA), and fine needle biopsy (FNB) are considered the best procedures for the diagnosis of biliopancreatic lesions. These methods represent a milestone since they proved to be both safe for the patient and useful to achieve diagnostic material useful to plan the best treatment strategy., Objective: Since in the literature, a debate between cytology and histology supporters is still ongoing and the trend is changing in favor of FNB, we would like to present our experience about the diagnostic yield of FNA and FNB. The aim of our study is to highlight FNA versus FNB diagnostic role of biliopancreatic lesions, highlight advantages, and drawbacks of these procedures, and our view on these 2 procedures and whether they should still be considered complementary or opposing techniques., Methods: We retrospectively reviewed our hospital series of 469 EUS diagnostics procedures of biliopancreatic lesions performed in 419 patients, between 2015 and 2019., Results: The overall adequacy rates of FNA and FNB were, respectively, 98.9 and 100%. Stratifying cases according to anatomic location of the mass (pancreas vs. biliary system), we detected 168 malignancies out of 349 pancreatic lesions (168/349; 48.1%), while biliary system cases positive for malignancy represented 33.8% (23/68 cases) (p value = 0.045, χ2 test). As for concomitant FNB, our series displayed a high rate of diagnostic concordance (88.8%)., Conclusions: Despite numerous data published, it is still unclear which is the most feasible method to use; therefore, we compared FNA, FNB, or their combination to understand the best applicable technique. Our experience confirmed that FNA is extremely efficient in the diagnosis of biliopancreatic lesions, especially in the hands of expert endoscopists and pathologists. Considering anatomic location, EUS-FNA is more accurate for mass-forming neoplasms in the pancreatic parenchyma rather than for lesions of the biliary system. Moreover, concomitant FNB usually confirmed the cytological diagnosis, allowing a deeper immunohistochemical characterization of the neoplasia. This proves that a "pure" cytology and "pure" histology approach should be looked differently since these are complementary techniques especially if we can obtain a cellblock from FNA., (© 2020 S. Karger AG, Basel.)

The recent advent of genome editing techniques and their rapid improvement paved the way in establishing innovative human neurological disease models and in developing new therapeutic opportunities. Human pluripotent (both induced or naive) stem cells and neural stem cells represent versatile tools to be applied to multiple research needs and, together with genomic snip and fix tools, have recently made possible the creation of unique platforms to directly investigate several human neural affections. In this chapter, we will discuss genome engineering tools, and their recent improvements, applied to the stem cell field, focusing on how these two technologies may be pivotal instruments to deeply unravel molecular mechanisms underlying development and function, as well as disorders, of the human brain. We will review how these frontier technologies may be exploited to investigate or treat severe neurodevelopmental disorders, such as microcephaly, autism spectrum disorder, schizophrenia, as well as neurodegenerative conditions, including Parkinson's disease, Huntington's disease, Alzheimer's disease, and spinal muscular atrophy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Building and functioning of the human brain requires the precise orchestration and execution of myriad molecular and cellular processes, across a multitude of cell types and over an extended period of time. Dysregulation of these processes affects structure and function of the brain and can lead to neurodevelopmental, neurological, or psychiatric disorders. Multiple environmental stimuli affect neural stem cells (NSCs) at several levels, thus impairing the normal human neurodevelopmental program. In this review article, we will delineate the main mechanisms of infection adopted by several neurotropic pathogens, and the selective NSC vulnerability. In particular, TORCH agents, i.e., Toxoplasma gondii , others (including Zika virus and Coxsackie virus), Rubella virus, Cytomegalovirus, and Herpes simplex virus, will be considered for their devastating effects on NSC self-renewal with the consequent neural progenitor depletion, the cellular substrate of microcephaly. Moreover, new evidence suggests that some of these agents may also affect the NSC progeny, producing long-term effects in the neuronal lineage. This is evident in the paradigmatic example of the neurodegeneration occurring in Alzheimer's disease.

The iron-deficiency anemia is a common disorder worldwide. It is widely treated with oral iron supplements as ferrous sulfate compound in pill or tablet form, and continuous therapy can induce gastric diseases. The diagnosis of this unusual drug-induced disease is based on the endoscopic findings and the histopathological biopsy examination, because the clinical symptoms are vague and non-specific. Herein we report five cases of iron pill-induced gastritis after oral ferrous sulfate administration. The aim of this report is to underline that iron pill-induced gastritis is an under-diagnosed entity that must be kept in mind when patients undergo chronic iron-pill therapy because it can carry severe upper digestive tract complications. Moreover, we would speculate about the potential tumorigenic role of iron intake in iron-induced gastric inflammation., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Onorati et al.)

Introduction: Bladder mucosa is anatomically covered by urothelial epithelium. The replacement of the urothelium with stratified squamous cells is defined as squamous metaplasia which can be keratinizing or non-keratinizing. Clinically, it is also known as leukoplakia or keratinizing cystitis of the bladder. Although several etiologic factors have been proposed such as chronic inflammation, irritative stimuli and infection, its pathogenesis is not clearly understood. The natural history of squamous metaplasia and clinical treatment are controversial. Many authors consider squamous metaplasia as a premalignant lesion, so it is fundamental to find an effective treatment to reduce the risk of developing bladder squamous carcinoma., Case Description: We report our management of a 58-year-old man with histological evidence of keratinizing squamous metaplasia and severe lower urinary tract symptoms. After repeated transurethral resections, the patient was treated with intravesical instillation of hyaluronic acid showing the regression of the lesion with an improvement of macroscopic appearance followed by the resolution of clinical symptoms., Conclusion: The therapeutic management of keratinizing squamous metaplasia is controversial, and currently no effective medical therapy is available for its treatment. Actually, patients undergo transurethral resections and a multidisciplinary approach is required to avoid cystectomy. Annual cystoscopy with multiple biopsies should be performed to determine the presence of dysplasia. Moreover, the therapeutic treatment with hyaluronic acid instillations could be the starting point and the gold standard in the follow-up of our patient. However, at present, further studies are required to formulate an adequate policy for therapeutic management of this unusual lesion of the bladder mucosa.

Periampullary neoplasms are a heterogeneous group of tumors arising within 2 cm of the ampulla of Vater. Neuroendocrine tumors can originate throughout the entire body, from neuroendocrine cells. These neoplasms exhibit deep differences, according to their origin and biological behavior. We describe a case of a 79-year-old man who underwent pancreaticoduodenectomy for adenocarcinoma of the ampulla of Vater after proper staging. At gross histology, an incidental pancreatic neuroendocrine tumor was also documented. Despite two synchronous neoplasms, the patient survived 34 months with no evidence of recurrence at follow-up. The synchronous presence of a second primitive tumor in patients affected by a neuroendocrine tumor is reported in the literature; incidence is variable and the most common site is the gastrointestinal tract. Diagnostic workup for ampullary neoplasms includes abdominal computed tomography (CT) scan, magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS). These investigations infrequently may detect subcentimetric lesions. We believe this case is currently extremely rare. Preoperative diagnosis of synchronous PanNET would not have changed our approach since surgical therapy represents the gold standard in resectable ampullary neoplasms, and it has a primary role in the prognosis of the present patient., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Viti et al.)

DACH1 is the human homolog of the Drosophila dachshund gene, which is involved in the development of the eye, nervous system, and limbs in the fly. Here, we systematically investigate DACH1 expression patterns during human neurodevelopment, from 5 to 21 postconceptional weeks. By immunodetection analysis, we found that DACH1 is highly expressed in the proliferating neuroprogenitors of the developing cortical ventricular and subventricular regions, while it is absent in the more differentiated cortical plate. Single-cell global transcriptional analysis revealed that DACH1 is specifically enriched in neuroepithelial and ventricular radial glia cells of the developing human neocortex. Moreover, we describe a previously unreported DACH1 expression in the human striatum, in particular in the striatal medium spiny neurons. This finding qualifies DACH1 as a new striatal projection neuron marker, together with PPP1R1B, BCL11B, and EBF1. We finally compared DACH1 expression profile in human and mouse forebrain, where we observed spatio-temporal similarities in its expression pattern thus providing a precise developmental description of DACH1 in the 2 mammalian species., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Synovial Sarcoma (SS) is the fourth most common soft tissue sarcoma, characterized by translocation t(X;18) (p11.2;q11.2). Although its histological features have been extensively described, this entity is characterized by a wide morphological spectrum so that the recognition can be very challenging at atypical anatomical localization, like the thyroid. We describe a case of a 42-ys-old female patient complaining a cervical swelling due to left intrathyroid nodule, measuring 35 mm in its greatest dimension. A Fine Needle Aspiration Cytology (FNAC) was performed and diagnosis of indeterminate neoplastic lesion, indefinite whether primary or metastatic, was formulated. After complete thyroidectomy, the histological picture of the nodule was characterized by a dual cellular population: several glandular structures composed by columnar cells with clear cytoplasm were embedded in a highly cellular stroma composed of spindle-shaped elements. Immunohistochemistry and molecular biology confirmed the morphological suspicion of SS identifying the fusion transcript SYT-SSX1 and thus ruling out several differential diagnoses which include more common thyroid malignancies. Moreover a synchronous papillary microcarcinoma was detected in the controlateral lobe., This case is noteworthy since it describes the synchronous presence in the thyroid of two completely different malignancies, the first one belonging to the soft tissue neoplasm category and the other one originating from the thyroid follicular epithelium., (Copyright © 2018 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Traumatic spinal cord injury results in persistent disability due to disconnection of surviving neural elements. Neural stem cell transplantation has been proposed as a therapeutic option, but optimal cell type and mechanistic aspects remain poorly defined. Here, we describe robust engraftment into lesioned immunodeficient mice of human neuroepithelial stem cells derived from the developing spinal cord and maintained in self-renewing adherent conditions for long periods. Extensive elongation of both graft and host axons occurs. Improved functional recovery after transplantation depends on neural relay function through the grafted neurons, requires the matching of neural identity to the anatomical site of injury, and is accompanied by expression of specific marker proteins. Thus, human neuroepithelial stem cells may provide an anatomically specific relay function for spinal cord injury recovery.

Objective: Basal cell adenoma (BCA) is an uncommon benign epithelial neoplasm of salivary glands, which was first described by Kleinsasser and Klein in 1967 and which derives its name from the monomorphic basaloid appearance of tumor cells. This tumor represents 1-2% of all salivary gland epithelial tumors; the most common site of occurrence is the parotid gland. It usually arises in adults over 50 years of age with slight female prevalence., Study Design: We analyzed 5 cases of parotid lesions investigated by fine needle aspiration cytology at a single institution between 2002 and 2018., Results: Our series was composed by 3 women and 2 men with a mean age of 62 years. The most important cytological criteria we observed were cohesive sharp-angled clusters of regular basaloid cells, palisaded by p63-positive myoepi-thelial cells, and bordered by basement membrane-like hyaline membrane in the absence of a myxochondroid stroma. Overall features were consistent with the diagnosis of BCA., Conclusions: Our aim is to highlight the cytological features of these rare lesions improving the awareness of cytological pitfalls of salivary gland basaloid neoplasms. Moreover, the goal of this paper is to add to the literature 5 additional cases of these unusual tumors., (© 2018 S. Karger AG, Basel.)

To better understand the molecular and cellular differences in brain organization between human and nonhuman primates, we performed transcriptome sequencing of 16 regions of adult human, chimpanzee, and macaque brains. Integration with human single-cell transcriptomic data revealed global, regional, and cell-type-specific species expression differences in genes representing distinct functional categories. We validated and further characterized the human specificity of genes enriched in distinct cell types through histological and functional analyses, including rare subpallial-derived interneurons expressing dopamine biosynthesis genes enriched in the human striatum and absent in the nonhuman African ape neocortex. Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels, with relevance for brain function and disease., (Copyright © 2017, American Association for the Advancement of Science.)

Introduction: The aims of this report are to illustrate the first case of glial and adipose tissue choristoma at the ventral part of the tongue in an elderly patient, to discuss the possible differential diagnoses and to speculate about its pathogenesis., Case Report: A 65-year-old female was admitted to our hospital with a swelling at the base of the tongue. MRI revealed an oval lesion with indistinct borders without contrast enhancement. The patient underwent surgical complete excision and grossly, the specimen consisted of a gray-white mass measuring 25 mm in its great diameter. Microscopically the lesion contained fibrocollagenous stroma, mature adipose tissue and mature astrocytes. In the absence of cellular atypia, mitoses and necrosis a diagnosis of adipose and glial choristoma was performed. The patient is healthy 18 months postoperatively., Discussion: Choristomas are cohesive tumor-like masses histologically composed by normal tissue occurring in an unusual anatomical location and mainly affecting children during the first years of life. Glial choristomas are considered malformations of the central nervous system and their localization in the tongue is exceptional. However they carry a favourable prognosis so it is of paramount importance to histologically diagnose them correctly.

In vertebrates, one main feature of stress response is the release of glucocorticoids (corticosterone in reptiles), steroid hormones whose synthesis is regulated by the hypothalamic-pituitary-adrenal axis (HPA). In the Galápagos Islands, populations of land iguanas are differentially impacted by a tick-transmitted apicomplexan hemoparasite of genus Hepatozoon , which could cause diseases and ultimately reduce fitness. Using competitive enzyme-linked immunosorbent assays (ELISA), we examined baseline plasma corticosterone levels of two syntopic and highly parasitized populations of the land iguana species Conolophus marthae and C. subcristatus in Wolf volcano (Isabela Island). We also used a poorly parasitized population of C. subcristatus from the same island (Bahia Urbina) as a reference. To better interpret the observed glucocorticoids patterns, we simultaneously performed the count of white blood cells (WBCs) in all individuals and investigated the reproductive status of females. We did not find evidence in support of either a positive or negative relationship between the tick load, hemoparasite infection, and glucocorticoid plasma concentration in C. marthae and C. subcristatus at Wolf volcano. The comparison between parasitized and non-parasitized sites (V. Wolf and Bahia Urbina) would instead suggest an inverse relationship between corticosterone and parasites. Our findings support association between corticosterone plasma levels and reproduction.

The mechanisms underlying Zika virus (ZIKV)-related microcephaly and other neurodevelopment defects remain poorly understood. Here, we describe the derivation and characterization, including single-cell RNA-seq, of neocortical and spinal cord neuroepithelial stem (NES) cells to model early human neurodevelopment and ZIKV-related neuropathogenesis. By analyzing human NES cells, organotypic fetal brain slices, and a ZIKV-infected micrencephalic brain, we show that ZIKV infects both neocortical and spinal NES cells as well as their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death. ZIKV infection of NES cells and RGCs causes centrosomal depletion and mitochondrial sequestration of phospho-TBK1 during mitosis. We also found that nucleoside analogs inhibit ZIKV replication in NES cells, protecting them from ZIKV-induced pTBK1 relocalization and cell death. We established a model system of human neural stem cells to reveal cellular and molecular mechanisms underlying neurodevelopmental defects associated with ZIKV infection and its potential treatment., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

In a combined approach, endocrine and ultrasonic analyses were performed to assess reproduction of two syntopic populations of terrestrial Galápagos iguanas the Conolophus marthae (the Galápagos Pink Land Iguana) and C. subcristatus on the Volcán Wolf (Isabela Island). The ELISA methods (enzyme-linked immunosorbent assay) were used to measure plasma concentrations of progesterone (P4) and 17β-estradiol (E2) from samples collected over the course of three different seasons: July 2010, June 2012-2014. As for C. subcristatus, the large number of females with eggs in 2012 and 2014 were associated with increased plasma P4 concentrations and the corresponding absence of females with eggs in July 2010 when concentrations of both hormones levels were basal indicating reproduction was still ongoing in June and had ended in July. In C. marthae, even though there was a positive relationship between egg-development stages and hormone concentrations, P4 concentrations were basal through the three years that samples were collected, with some females having a lesser number of eggs compared with C. subcristatus. In C. marthae P4 and E2 patterns did not allow for defining a specific breeding season., (Copyright © 2016 Elsevier B.V. All rights reserved.)

HMGA proteins are small nuclear proteins that bind DNA by conserved AT-hook motifs, modify chromatin architecture and assist in gene expression. Two HMGAs (HMGA1 and HMGA2), encoded by distinct genes, exist in mammals and are highly expressed during embryogenesis or reactivated in tumour progression. We here addressed the in vivo role of Xenopus hmga2 in the neural crest cells (NCCs). We show that hmga2 is required for normal NCC specification and development. hmga2 knockdown leads to severe disruption of major skeletal derivatives of anterior NCCs. We show that, within the NCC genetic network, hmga2 acts downstream of msx1, and is required for msx1, pax3 and snail2 activities, thus participating at different levels of the network. Because of hmga2 early effects in NCC specification, the subsequent epithelial-mesenchymal transition (EMT) and migration of NCCs towards the branchial pouches are also compromised. Strictly paralleling results on embryos, interfering with Hmga2 in a breast cancer cell model for EMT leads to molecular effects largely consistent with those observed on NCCs. These data indicate that Hmga2 is recruited in key molecular events that are shared by both NCCs and tumour cells., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The aim of the current case report is to re-evaluate the key features and pitfalls of fine-needle aspiration cytology (FNAC) in the diagnosis of sclerosing pneumocytoma (previously named sclerosing hemangioma) and to establish the importance of FNAC in addressing a proper surgical strategy., Case: Herein we documented a case of a 70- year-old man with a lung nodule which showed a hypermetabolic uptake on positron emission tomography. He therefore underwent FNAC under computed tomography scan guidance with a 22-gauge needle. The cytopathological examination allowed a diagnosis of sclerosing pneumocytoma. A wedge surgical excision was performed and the histological examination confirmed the cytological diagnosis., Conclusion: FNAC is a fundamental tool for distinguishing sclerosing pneumocytoma from a malignant lung tumour and together with clinical, radiological and pathological multidisciplinary assessment is indispensable in planning appropriate surgical management. Cytopathologists should be aware of the pitfalls and key features of the cytopathological diagnosis of sclerosing pneumocytoma, which can significantly change the surgical approach to the patient and protect him from aggressive overtreatment., (© 2016 S. Karger AG, Basel.)

Thyroid gland is one of the most vascularized organs of the body, nevertheless clinical and surgical series report an incidence of secondary malignancies in this gland of only 3%. Colorectal carcinoma metastatic to the thyroid gland is not as uncommon as previously believed, infact the number of cases seems to be increased in recent years due to the more frequent use of fine-needle aspiration cytology (FNAC) guided by ultrasonography. Although kidney, breast and lung metastases to the thyroid are frequent, metastasis from colon cancer is clinically rare with 52 cases reported in the literature in the last 5 decades and three cases described as solitary thyroid metastasis from the colon cancer without any other visceral metastases. To the best of our knowledge, we report the fourth case of solitary, asymptomatic thyroid metastasis from colon cancer without involvement of other organs. We discuss the importance of FNAC to detect metastatazing process as a compulsory step of the diagnostic and therapeutic management algorithm, combined with a molecular biology approach. A review of the last 5 decades literature, to update the number of cases described to date, is also included.

Translationally controlled tumor protein is a multifaceted protein involved in several physiological and biological functions. Its expression in normal kidney and in renal carcinomas, once corroborated by functional data, may add elements to elucidate renal physiology and carcinogenesis. In this study, translationally controlled tumor protein expression was evaluated by quantitative real time polymerase chain reaction and western blotting, and its localization was examined by immunohistochemistry on 84 nephrectomies for cancer. In normal kidney protein expression was found in the cytoplasm of proximal and distal tubular cells, in cells of the thick segment of the loop of Henle, and in urothelial cells of the pelvis. It was also detectable in cells of renal carcinoma with different pattern of localization (membranous and cytoplasmic) depending on tumor histotype. Our data may suggest an involvement of translationally controlled tumor protein in normal physiology and carcinogenesis. However, functional in vitro and in vivo studies are needed to verify this hypothesis.

Background: Primary effusion lymphoma (PEL) is a Kaposi's sarcoma-associated herpesvirus (KSHV)-related large B-cell lymphoma often affecting immunocompromised adults. However, several cases in nonimmunocompromised elderly patients have been reported. It usually occurs as a massive, serosal effusion without tumoral masses and lymphadenopathies. The most frequent diagnostic materials are cytological smears, displaying large lymphocytes with variable morphological aspects but with a specific 'null-cell' phenotype associated with the expression of KSHV-related latency-associated nuclear antigen., Cases: We report 2 cases of PEL that occurred in elderly, HIV-uninfected patients. In the first case, an 83-year-old man presented with severe dyspnea of 1 week duration. Radiological images documented pericardial effusion causing cardiac tamponade, without lymphadenopathies and solid masses. In the second case, an HIV-uninfected 94-year-old man was affected by anorexia, fatigue, shortness of breath and nonproductive cough. Radiological studies revealed bilateral pleural effusion, without evidence of abnormal lymphadenopathies and lung and/or pleural masses. Thoracentesis was immediately performed. Cytological evaluations of pericardial (first case) and pleural (second case) fluid effusion showed anaplastic and immunoblastic lymphocytes, respectively, expressing LCA/CD45, CD30 and KSHV., Conclusion: Albeit rare, PEL should be kept in mind in the diagnostic algorithm of serosal cytological evaluation in elderly HIV-uninfected patients., (© 2015 S. Karger AG, Basel.)

The complexity of the human brain derives from the intricate interplay of molecular instructions during development. Here we systematically investigated gene expression changes in the prenatal human striatum and cerebral cortex during development from post-conception weeks 2 to 20. We identified tissue-specific gene coexpression networks, differentially expressed genes and a minimal set of bimodal genes, including those encoding transcription factors, that distinguished striatal from neocortical identities. Unexpected differences from mouse striatal development were discovered. We monitored 36 determinants at the protein level, revealing regional domains of expression and their refinement, during striatal development. We electrophysiologically profiled human striatal neurons differentiated in vitro and determined their refined molecular and functional properties. These results provide a resource and opportunity to gain global understanding of how transcriptional and functional processes converge to specify human striatal and neocortical neurons during development.

Background: T-cell lymphoblastic lymphoma comprises approximately 85-90% of all lymphoblastic lymphomas. It often arises as a mediastinal mass, and with bone marrow involvement. Presentation at other sites without nodal or mediastinal localization is uncommon., Case Report: We describe clinical, histologic, immunohistochemical, and molecular features of two cases of primary T-cell lymphoblastic lymphoma arising respectively in uterine corpus and testis. The tumors were composed by medium to large cells, exhibiting a diffuse pattern of growth but sometimes forming indian files or pseudo-rosettes. The neoplastic cells strongly expressed TdT and T-cell markers in both uterine corpus and testis. However, the testis case also showed aberrant expression of B-cell markers, thus molecular biology was necessary to achieve a final diagnosis. T-cell receptor gene rearrangement analysis identified a T-cell origin., Conclusions: To the best of our knowledge, only one doubtful previous case of primary uterine T-cell lymphoblastic lymphoma and no previous cases of primary testicular T-cell lymphoblastic lymphoma have been reported. Due to the morphology of neoplastic cells, a challenging differential diagnosis with all the tumors belonging to the so-called small round blue cell tumor category is mandatory. In ambiguous lineage cases, molecular biology may represent an adequate tool to confirm diagnosis., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1559880973128230.

The clinical presentation of two different digestive diseases such as Crohn's disease and intestinal tuberculosis may be so similar to induce a delay in correct diagnosis and appropriate treatment (immune suppression versus antibiotic therapy). Herein, we describe the case of a young man from Eastern Europe who came to our observation complaining of clinical symptoms initially misdiagnosed as an inflammatory bowel disease. It is important to keep in mind the possibility of an active tubercular disease, particularly in patients coming from countries endemic for the disease. Morphological findings of sarcoid-like granulomas at biopsy is not enough for a conclusive diagnosis of Crohn's disease, and tuberculosis should be ruled out on the basis of clinical information, laboratory tests and radiological imaging.

Background: The incidence of gastric metastasis is 2.6%. Although all primary neoplasms can metastasize to the stomach, most originate from melanoma or breast and lung cancer. Their most common endoscopic appearance is a "volcano-like" polypoid mass covered by normal mucosa that may show a central ulceration. Renal cell carcinoma, clear cell type, is known to spread hematogenously, and isolated metastasis to the stomach is a rare event., Case Presentation: In this report, we describe a gastric recurrence of RCC, clear-cell type, in a 80-year-old patient who had undergone nephrectomy 20 years before. We also performed a brief review of the literature to update the number of cases described to date., Conclusion: Metastatic involvement of the stomach should be suspected in any patient with a previous history of renal cell carcinoma, clear cell type, presenting with gastrointestinal symptoms, even if many years after nephrectomy. The peculiarity of our case is due to the very late presentation of the gastric metastasis. Only two cases of very late gastric metastases from RCC, clear cell type, have been described in the literature, to date.

Here we present the principles and steps of a protocol that we have recently developed for the differentiation of hES/iPS cells into the authentic human striatal projection medium spiny neurons (MSNs) that die in Huntington's Disease (HD). Authenticity is judged by the convergence of multiple features within individual cells. Our procedure lasts 80 days and couples neural induction via BMP/TGF-β inhibition with exposure to the developmental factors sonic hedgehog (SHH) and dickkopf1 (DKK-1) to drive ventral telencephalic specification, followed by terminal differentiation [1]. Authenticity of the resulting neuronal population is monitored by the appearance of FOXG1(+)/GSX2(+) progenitor cells of the lateral ganglionic eminence (LGE) at day 15-25 of differentiation, followed by appearance of CTIP2-, FOXP1- and FOXP2-positive cells at day 45. These precursor cells then mature into MAP2(+)/GABA(+) neurons with 20 % of them ultimately co-expressing the DARPP-32 and CTIP2 diagnostic markers and carrying electrophysiological properties expected for fully functional MSNs.The protocol is characterized by its replicability in at least three human pluripotent cell lines. Altogether this protocol defines a useful platform for in vitro developmental neurobiology studies, drug screening, and regenerative medicine approaches.

High Mobility Group A proteins (HMGA1 and HMGA2) are architectural nuclear factors involved in development, cell differentiation, and cancer formation and progression. Here we report the cloning, developmental expression and functional analysis of a new multi-AT-hook factor in Xenopus laevis (XHMG-AT-hook) that exists in three different isoforms. Xhmg-at-hook1 and 3 isoforms, but not isoform 2, are expressed throughout the entire development of Xenopus, both in the maternal and zygotic phase. Localized transcripts are present in the animal pole in the early maternal phase; during the zygotic phase, mRNA can be detected in the developing central nervous system (CNS), including the eye, and in the neural crest. We show evidence that XHMG-AT-hook proteins differ from typical HMGA proteins in terms of their properties in DNA binding and in protein/protein interaction. Finally, we provide evidence that they are involved in early CNS development and in neural crest differentiation.

Leiomyomatosis peritonealis disseminata (LPD) is a rare smooth muscle tumour characterized by multiple small nodules on the omentum and peritoneal surface, composed of benign smooth muscle cells with minimal mitotic activity, frequently admixed with decidual cells. The possible pathogenetic mechanisms include hormonal dysfunction, differentiation of subperitoneal mesenchymal stem cells, myofibroblastic metaplasia and genetic and iatrogenic causes (resection of myomas during laparoscopic surgery). Diagnosis is easily made on biopsy specimens. Reduction of oestrogen exposure, surgical castration or gonadotrophin releasing hormone agonists are generally sufficient to cause regression of LPD. We report a case of an asymptomatic 36-year-old pregnant woman with long-term use of oral contraceptives, and previous myomectomy, who had a mass of uncertain origin which was, histopathologically, diagnosed as leiomyomatosis peritonealis diffusa with foci of ectopic decidua. Ectopic decidua was also present in a pelvic lymph node. To the best of our knowledge, this is the first case of LPD containing foci of ectopic decidua in a pregnant woman with a past history of myomectomy and use of oral contraception for three years; ectopic decidua was also detected in a pelvic lymph node.

We have developed a simple method to generate and expand multipotent, self-renewing pre-rosette neural stem cells from both human embryonic stem cells (hESCs) and human induced pluripotent stem cells (iPSCs) without utilizing embryoid body formation, manual selection techniques, or complex combinations of small molecules. Human ESC and iPSC colonies were lifted and placed in a neural stem cell medium containing high concentrations of EGF and FGF-2. Cell aggregates (termed EZ spheres) could be expanded for long periods using a chopping method that maintained cell-cell contact. Early passage EZ spheres rapidly down-regulated OCT4 and up-regulated SOX2 and nestin expression. They retained the potential to form neural rosettes and consistently differentiated into a range of central and peripheral neural lineages. Thus, they represent a very early neural stem cell with greater differentiation flexibility than other previously described methods. As such, they will be useful for the rapidly expanding field of neurological development and disease modeling, high-content screening, and regenerative therapies based on pluripotent stem cell technology., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Laryngeal chondrosarcomas are rare tumours that account for less than 1% of all sarcomas and originate principally from the crycoid cartilage. We report two cases: the former arising from thyroid cartilage in an 85-year-old male presenting with a palpable neck mass and hoarseness, dyspnoea and dysphagia; the other in a 54-year-old male with a mass growing from crycoid cartilage, who underwent biopsy followed by total laryngectomy. We discuss the peculiarity of the site of origin and the role of biopsy, the clinical presentation of the former case and the diagnostic and therapeutic procedures of the latter. Since it is a rare form of sarcoma arising in the larynx, we discuss the role of biopsy as a crucial although still controversial diagnostic tool.