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The outbreak of COVID‐19 forced national governments and health authorities worldwide to adopt measures aimed at protecting population health, most of which resulted in prolonged restrictions to individual freedom(s) and fundamental rights. In some cases, the pandemic represented a pretext for macroscopic and unjustified human rights violations, as in the case of the "ferry quarantine," that is the use of commercial boats by the Italian Government to forcibly isolate migrants and asylum seekers from the rest of the population. Such a measure does not have any rationale at the epidemiological level and poses serious obstacles to the provision of adequate care to vulnerable people such as migrants and asylum seekers. The pandemic has been used as a pretext to implement discriminatory and disproportionate measures whose effect has been denying healthcare access to undocumented migrants and asylum seekers. [ABSTRACT FROM AUTHOR]

Telemedicine is increasingly being considered as a viable solution to advance healthcare organization, widening accessibility and increasing the quality of service delivery. However, implementing telemedicine in prison settings is not unproblematic as it gives rise to a range of ethical issues. In light of this, this article seeks to provide an ethical perspective for prison telemedicine, offered as a point of departure for stimulating a better integration of telemedicine in correctional systems. This entails examining this innovation as part of a wider strategy aimed at fully addressing the medical needs of prison populations. [ABSTRACT FROM AUTHOR]

NSD1, NSD2 and NSD3 proteins constitute a family of histone 3 lysine 36 (H3K36) methyltransferases with similar domain architecture, but diversified activities, in part, dependent on their non‐enzymatic domains. These domains, despite their high sequence identity, recruit the hosting proteins to different chromatin regions through the recognition of diverse epigenetic marks and/or associations to distinct interactors. In this sense, the PHDvC5HCH finger tandem domain represents a paradigmatic example of functional divergence within the NSD family. In this work, we prove and give a structural rationale for the uniqueness of the PHDvC5HCH domain of NSD1 in recognizing the C2HR Zinc finger domain of Nizp1 (NSD1 interacting Zn finger protein). Importantly, we show that, in a leukaemogenic context, Nizp1 is pivotal in driving the unscheduled expression of HoxA genes and of genes involved in the type I IFN pathway, triggered by the expression of the fusion protein NUP98‐NSD1. These data provide the first insight into the pathophysiological relevance of the Nizp1‐NSD1 functional association. Targeting of this interaction might open new therapeutic windows to inhibit the NUP98‐NSD1 oncogenic properties. [ABSTRACT FROM AUTHOR]

Since the very emergence of the information technologies in healthcare, a major concern has been raised about the potential of remote services to undermine the intimacy, immediacy and humanity intrinsic to conventional, face-to-face medical practice. By contrast, notable literature reports the benefits of information technology–mediated services and their potential to improve efficiency and economic convenience of healthcare systems. This article aims to shed light on this ambivalence by retracing the evolution of doctor–patient interaction in relation to the main technological advancements in healthcare, and in particular, to services mediated by information technologies. Consequently, the reduction of cues and clues associated with the use of these services is framed into the reductionism of the biomedical paradigm, which provides a key to interpret the nature, scope and features of this process of technological innovation, along with its potential and limits. [ABSTRACT FROM AUTHOR]

Over the last two decades, a public rationale for the implementation of telehealth has emerged at the interplay of specialised literature and political orientations. Despite the lack of consistent findings on the magnitude of its benefits, telehealth is nowadays presented as a worthy solution both for patients and healthcare institutions. Far from denying the potential advantages of telehealth, the main objective of this work is to provide a critical assessment on the spread of the remote services as a vector of positive transformation of contemporary health systems. For pursuing this objective, the EU agenda for the promotion of telehealth will be retraced, and the main evidences alleged to sustain the implementation of remote care services will be assessed. Furthermore, it will be evaluated the attempt made by the European Commission to establish an ethical framework for guiding the use of telehealth in daily practice, and a roadmap of the most relevant legal and ethical issues posed by the spread of telehealth will be traced. In the conclusions, it will be argued that the radical transformations induced by this form of technological innovation call on to a new, ad hoc ethics through which critically evaluate benefits and implications of telehealth services, with a view to keep high the standard of healthcare against the economic interests of private stakeholders and ICTs' vendors. [ABSTRACT FROM AUTHOR]

Motivation Single-cell profiling has become a common practice to investigate the complexity of tissues, organs, and organisms. Recent technological advances are expanding our capabilities to profile various molecular layers beyond the transcriptome such as, but not limited to, the genome, the epigenome, and the proteome. Depending on the experimental procedure, these data can be obtained from separate assays or the very same cells. Yet, integration of more than two assays is currently not supported by the majority of the computational frameworks avaiable. Results We here propose a Multi-Omic data integration framework based on Wasserstein Generative Adversarial Networks suitable for the analysis of paired or unpaired data with a high number of modalities (>2). At the core of our strategy is a single network trained on all modalities together, limiting the computational burden when many molecular layers are evaluated. Availability and implementation Source code of our framework is available at https://github.com/vgiansanti/MOWGAN [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to identify modifications in health, economic and social determinants of quality of life (QoL) in community-dwelling older adults when using different cut-offs to defining favorable QoL.Methods: Data of year 2011 annual assessment in 1003 older men and women from the Lc65+ cohort study were used. Overall QoL was self-rated as 'excellent,' 'very good,' 'good,' 'fair,' or 'poor.' To identify significant health (self-rated health, SF-12v2 physical and mental health), economic (financial situation), and social (living with others, being socially supported, emotional support, group activities participation) determinants of QoL, a cut-off was set at three different positions to define favorable QoL on the 'excellent' to 'poor' spectrum: at least 'good' (model 1); at least 'very good' (model 2); and 'excellent' only (model 3).Results: In all three models, bivariable analyses indicated significant associations between QoL and at least one variable from each health, economic, and social dimension. In multivariable analyses, only health-related variables remained significantly associated with QoL in model 1. Model 3 additionally retained financial situation. In model 2, QoL was positively associated with physical health [odds ratio (OR) 1.10, p < 0.001], mental health (OR 1.12, p < 0.001), self-rated health (OR 2.43, p < 0.001), group activities participation (OR 1.43, p = 0.037), being socially supported (OR 1.58, p = 0.024), and not reporting financial difficulties (OR 1.76; p = 0.036).Conclusions: Using different cut-offs to defining favorable QoL results in important changes in the number and type of significant health, economic and social determinants. A cut-off between 'good' and 'very good' appears to best reflect the multidimensional nature of QoL. [ABSTRACT FROM AUTHOR]

We report the stereoselective synthesis and biological activity of a novel series of tranylcypromine (TCPA) derivatives (14a-k, 15, 16), potent inhibitors of KDM1A. The new compounds strongly inhibit the clonogenic potential of acute leukemia cell lines. In particular three molecules (14d, 14e, and 14g) showing selectivity versus MAO A and remarkably inhibiting colony formation in THP-1 human leukemia cells, were assessed in mouse for their preliminary pharmacokinetic. 14d and 14e were further tested in vivo in a murine acute promyelocytic leukemia model, resulting 14d the most effective. Its two enantiomers were synthesized: the (1S,2R) enantiomer 15 showed higher activity than its (1R,2S) analogue 16, in both biochemical and cellular assays. Compound 15 exhibited in vivo efficacy after oral administration, determining a 62% increased survival in mouse leukemia model with evidence of KDM1A inhibition. The biological profile of compound 15 supports its further investigation as a cancer therapeutic. [ABSTRACT FROM AUTHOR]

Histone demethylase KDM1A (also known as LSD1) has become an attractive therapeutic target for the treatment of cancer as well as other disorders such as viral infections. We report on the synthesis of compounds derived from the expansion of tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. These compounds, which are substituted on the cyclopropyl core moiety, were evaluated for their ability to inhibit KDM1A in vitro as well as to function in cells by modulating the expression of Gfi-1b, a well recognized KDM1A target gene. The molecules were all found to covalently inhibit KDM1A and to become increasingly selective against human monoamine oxidases MAO A and MAO B through the introduction of bulkier substituents on the cyclopropylamine ring. Structural and biochemical analysis of selected trans isomers showed that the two stereoisomers are endowed with similar inhibitory activities against KDM1A, but form different covalent adducts with the FAD co-enzyme. [ABSTRACT FROM AUTHOR]

Aberrant recruitment of histone deacetylases (HDACs) by the oncogenic fusion protein PML-RAR is involved in the pathogenesis of acute promyelocytic leukemia (APL). PML- RAR, however, is not sufficient to induce disease in mice but requires additional oncogenic lesions during the preleukemic phase. Here, we show that knock-down of Hdac1 and Hdac2 dramatically accelerates leukemogenesis in transgenic preleukemic mice. These events are not restricted to APL because lymphomagenesis driven by deletion of p53 or, to a lesser extent, by c-myc overexpression, was also accelerated by Hdac1 knock-down. In the preleukemic phase of APL, Hdac1 counteracts the activity of PML-RAR in (1) blocking differentiation; (2) impairing genomic stability; and (3) increasing self-renewal in hematopoietic progenitors, as all of these events are affected by the reduction in Hdac1 levels. This led to an expansion of a subpopulation of PML-RAR-expressing cells that is the major source of leukemic stem cells in the full leukemic stage. Remarkably, short-term treatment of preleukemic mice with an HDAC inhibitor accelerated leukemogenesis. In contrast, knock-down of Hdac1 in APL mice led to enhanced survival duration of the leukemic animals. Thus, Hdacl has a dual role in tumorigenesis: oncosuppressive in the early stages, and oncogenic in established tumor cells. [ABSTRACT FROM AUTHOR]

The aim of the study was to analyze the frequency of incidental thyroid carcinoma (unknown tumor smaller than or equal to 10 mm) in a consecutive series of 462 total thyroidectomies for multinodular goiter and to investigate the clinical risk factors for this type of malignancy. A retrospective, single-center study of outcome data collected from patients with preoperative diagnosis of multinodular goiter who underwent total thyroidectomy at the General Surgery Unit of Pavia (Italy) between January 2000 and December 2008 was performed. Possible risk factors for malignancy were: gender, age, time of evolution of goiter, presence of a dominant nodule in multinodular goiter, hyperthyroidism, history of radiation to the neck, residence in an area of endemic goiter, prior thyroid surgery, calcifications in the goiter detected by neck ultrasound or chest X-rays, and a family history of thyroid diseases. In a 9-year period, 462 patients underwent total thyroidectomy. We found 41 cases of incidental thyroid carcinoma; the most common histopathological type was papillary. The multivariable analysis demonstrated that the clinical variables associated with occult carcinoma were a personal history of radiation therapy to the neck, the presence of calcifications detected by ultrasound or neck X-rays, and a family history of thyroid diseases; residence in an area of endemic goiter was a protective factor. A personal history of radiation to the neck, detection of calcifications by ultrasound or by neck X-rays, and a family history of thyroid diseases should be considered clinical risk factors for malignancy in multinodular goiter. [ABSTRACT FROM AUTHOR]

In our study, we arbitrarily define complex hydatid cysts of the liver as either cysts with a diameter ≥ 10 cm, or as multiple and recurrent cysts. These types of cysts were then divided into two subgroups: giant cyst identified as a cyst with a diameter ≥ 10 cm, and complicated cyst as multiple, recurrent, abscessed cysts, or those resistant to conservative treatment. The aim of this study was to retrospectively analyze a series of 38 consecutive patients who underwent surgery for complex hydatid cysts over a period of 9 years at the same institute to determine the evolution of the surgical treatment and the risk factors for recurrence. Fourteen (36.8%) of these patients were women and 24 (63.2%) men (median age 48.1; range 16-71 years). The mean postoperative follow-up was 24 ± 10.8 months. All patients were treated prophylactically with albendazole (10 mg/Kg/ day) for 15 days preoperatively and for 2 months postoperatively. Partial cystectomy was performed in two cases (5.26%) and radical pericystectomy in 20 cases (52.63%). In 15 cases the patients underwent liver resection (39.47%): left hepatectomy was performed in eight cases (21.05%), and right hepatectomy in seven cases (18.42%). In one case, both wedge resection and pericystectomy were performed. There were no deaths and only one patient (2.63%) showed signs of recurrence at follow-up. Radical surgery is the most effective treatment for complex hydatid cysts. In our experience, partial or total pericystectomy virtually eliminated, over time, the need for hepatic resection. [ABSTRACT FROM AUTHOR]

Abstract: Absent or altered differentiation is one of the major features of cancer cells. Histone deacetylases (HDACs) play a central role in the epigenetic regulation of gene expression. Aberrant activity of HDACs has been documented in several types of cancers, leading to the development of HDAC inhibitors (HDACi) as anti-tumor drugs. In vitro and in vivo experimental evidences show that HDACi are able to resume the process of maturation in undifferentiated cancer cells, justifying their introduction as differentiating agents in several clinical trials. Modulation of cell fate by HDACi is observed at several levels, including the stem cell compartment: HDACi can act both on cancer stem cells, and with the rest of the tumor cell mass, leading to complex biological outputs. As a note of caution, when used as single agent, HDACi show only a moderate and limited biological response, which is augmented in combinatorial therapies with drugs designed against other epigenetic targets. The optimal employment of these molecules may be therefore in combination with other epigenetic drugs acting against the set of enzymes responsible for the set-up and maintenance of epigenetic information. [Copyright &y& Elsevier]

Simple Summary: Genomic instability is recognized as a driving force in most cancers as well as in the haematological cancer multiple myeloma and remains among the leading cause of drug resistance. Several evidences suggest that replicative stress exerts a fundamental role in fuelling genomic instability. Notably, cancer cells rely on a single protein, ATR, to cope with the ensuing DNA damage. In this perspective, we provide an overview depicting how replicative stress represents an Achilles heel for multiple myeloma, which could be therapeutically exploited either alone or in combinatorial regimens to preferentially ablate tumor cells. Multiple Myeloma (MM) is a genetically complex and heterogeneous hematological cancer that remains incurable despite the introduction of novel therapies in the clinic. Sadly, despite efforts spanning several decades, genomic analysis has failed to identify shared genetic aberrations that could be targeted in this disease. Seeking alternative strategies, various efforts have attempted to target and exploit non-oncogene addictions of MM cells, including, for example, proteasome inhibitors. The surprising finding that MM cells present rampant genomic instability has ignited concerted efforts to understand its origin and exploit it for therapeutic purposes. A credible hypothesis, supported by several lines of evidence, suggests that at the root of this phenotype there is intense replicative stress. Here, we review the current understanding of the role of replicative stress in eliciting genomic instability in MM and how MM cells rely on a single protein, Ataxia Telangiectasia-mutated and Rad3-related protein, ATR, to control and survive the ensuing, potentially fatal DNA damage. From this perspective, replicative stress per se represents not only an opportunity for MM cells to increase their evolutionary pool by increasing their genomic heterogeneity, but also a vulnerability that could be leveraged for therapeutic purposes to selectively target MM tumor cells. [ABSTRACT FROM AUTHOR]

Abstract: G protein-coupled receptor kinase interactors (GITs) are adaptor proteins with ADP-ribosylating factor – GTPase-activating protein (ARF–GAP) activity that form complexes with the p21-activated kinase-interacting exchange factor (PIX) guanine nucleotide exchanging factors for Rac and Cdc42. In this study we have characterized the endogenous GIT1/p95-APP1/Cat1 (GIT1)– PIX complexes in neuronal and non-neuronal cells. In COS7 cells, immunocytochemical analysis shows the localization of endogenous GIT1 in the perinuclear region of the cell, as well as at the cell periphery, where GIT1 co-localizes with filamentous actin. The perinuclear localization of endogenous GIT1 was confirmed in avian fibroblasts. In COS7 cells, immunoprecipitation and microsequencing experiments with either anti-GIT1 or anti-βPIX antibodies unequivocally show that βPIX is uniquely associated with GIT1 in lysates from these cells, while GIT2/PKL/p95-APP2/Cat2 (GIT2) is undetectable in the endogenous complexes. Moreover, this analysis demonstrates that βPIX is the limiting factor for the formation of the endogenous complexes, since a small fraction of GIT1 can be co-immunoprecipitated with most βPIX from these cells. Saponin treatment of unfixed cells indicates that βPIX-bound GIT1 is preferentially retained in the saponin-resistant fraction when compared to βPIX-free GIT1. Moreover, analysis by tissue fractionation shows that a significant fraction of the endogenous GIT1–βPIX complex is firmly associated to membranes from brain homogenates. Our findings show the specific localization of the complex at intracellular membranes, and indicate a correlation between the association of GIT1 to βPIX, and the localization of the endogenous complex at membranes. [Copyright &y& Elsevier]

Abstract: The cross sections for neutrino scattering off the 12C and 16O nuclei are calculated within the framework of the continuum Random Phase Approximation. A model to consider also the final state interactions is developed. Total charge-conserving and charge-exchange cross sections for both electron neutrinos and antineutrinos have been calculated up to projectile energies of 100 MeV. The sensitivity of the cross sections to the residual interaction and to the final state interactions is investigated. A direct comparison between neutrino and electron scattering cross sections calculated under the same kinematic conditions is presented. We found remarkable differences between electromagnetic and weak nuclear responses. The model is applied to describe cross sections of neutrinos produced by muon decay at rest and in supernovae explosions. [Copyright &y& Elsevier]

We discuss some differences and similarities between electron and neutrino scattering off atomic nuclei. We find that, in the giant resonance region, the two processes excite different nuclear modes, therefore the weak and the electromagnetic nuclear responses are rather different. In any case, the scattering of electrons and photons is the best guide we have to test the validity of our nuclear models and their prediction power. The experience in describing electromagnetic excitations of the nucleus, suggests that, when the nucleus is excited in the continuum, the re-interaction between the emitted nucleon and the remaining nucleus should not be neglected. A simple model taking into account this final state interaction is proposed, and applied to the neutrino scattering off16O nucleus.PACS:25.30.Pt Neutrino scattering - 24.30.Cz Giant resonances [ABSTRACT FROM AUTHOR]

LRH-1 is an orphan nuclear receptor predominantly expressed in tissues of endodermal origin, where it controls development and cholesterol homeostasis. We show here that LRH-1 induces cell proliferation through the concomitant induction of cyclin D1 and E1, an effect that is potentiated by its interaction with β-catenin. Whereas β-catenin coactivates LRH-1 on the cyclin E1 promoter, LRH-1 acts as a potent tissue-restricted coactivator of β-catenin on the cyclin D1 promoter. The implication of LRH-1 in cell proliferation highlights an unanticipated crosstalk between LRH-1 and the β-catenin/Tcf4 signaling pathway, which is relevant for the renewal of intestinal crypt cells. [Copyright &y& Elsevier]

Investigates the effect of endothelial cyclooxygenase (COX)-1 and -2 on the reactivity of the mesenteric vascular bed (MVB) in portal hypertensive rats. Expression of constitutive and inducible COX; Role of prostanoids in the aorta in the MVB; Data suggesting that generation of endothelial vasodilator prostanoids accounts for the increased mesenteric blood flow in portal hypertension.

Background: The Go Wish Game (GWG) is a practical tool developed to ease advance care planning (ACP) conversations regarding end-of-life (EOL) issues. The game consists of a guide and 35 cards to help persons think about their personal values and priorities in the context of care and to discuss and share those concerns with families and health care professionals (HPs). Objectives: To promote ACP conversations in the Italian context, we developed an Italian version of the GWG by linguistic translation and cultural adaptation. Design: Cross-cultural adaptation process developed by Beaton et al. Measurements: We started with a back-and-forth translation to guarantee linguistic appropriateness. A prefinal Italian version was developed and then qualitatively evaluated by two focus groups (FGs) to assess content validity and cultural appropriateness. Participants' suggestions were discussed by the research groups and included in the final Italian version. Data analysis: The FGs' transcripts were analyzed by thematic analysis. Sample: One FG included HPs potentially involved in ACP, the second FG involved representative from local patient associations (RLPAs) with chronic, degenerative, and potentially terminal disease. Participants were purposefully selected. The two FGs involved eight HPs and five RLPAs, respectively. Results: Fewer explicit statements concerning EOL choices and a broader emphasis on the role of HPs in this discussion characterized the prefinal version. Our analysis identified three themes and five subthemes: (1) improving translation: linguistic redefinition and practical clarification; (2) how to play the GWG: needs and suggestions; and (3) more than a game. Conclusion: The Italian version developed in this study presents several cultural peculiarities. The rigorous translation and cultural adaptation process applied can enrich the existing literature by spreading a practical tool for initiating ACP in other languages and cultures. Further studies are needed to evaluate this tool's effectiveness in supporting ACP and training HPs to promote the ACP process. [ABSTRACT FROM AUTHOR]

Abstract: Soft X-ray diagnostic systems and their successful application in the field of magnetic fusion plasma physics are discussed. Radiation with wavelength in the region of Soft X-Ray (1–30keV) is largely produced by high temperature plasmas, carrying important information on many processes during a plasma discharge. Soft X-ray diagnostics are largely used in various fusion devices all over the world. These diagnostic systems are able to obtain information on electron temperature, electron density, impurity transport, Magneto Hydro Dynamic instabilities. We will discuss the SXR diagnostic installed on FTU in Frascati (Italy) and on Tore Supra in Cadarache (France), with special emphasis on diagnostic performances. Moreover, we will discuss the two different inversion methods for tomographic reconstruction used in Frascati and in Cadarache, the first one is relied on a guessed topology of iso-emissivity surfaces, the second one on regularization techniques, like minimum Fisher or maximum entropy. Finally, a new and very fast 2D imaging system with energy discrimination and high time resolution will be summarized as an alternative approach of SXR detection system. [ABSTRACT FROM AUTHOR]

The article describes the case of a female infant with hemangioma.

Leukemia-associated fusion proteins establish aberrant transcriptional programs, which result in the block of hematopoietic differentiation, a prominent feature of the leukemic phenotype. The dissection of the mechanisms of deregulated transcription by leukemia fusion proteins is therefore critical for the design of tailored antileukemic strategies, aimed at reestablishing the differentiation program of leukemic cells. The acute promyelocytic leukemia (APL)-associated fusion protein PML-retinoic acid receptor (RAR) behaves as an aberrant transcriptional repressor, due to its ability to induce chromatin modifications (histone deacetylation and DNA methylation) and silencing of PML-RAR target genes. Here, we indicate that the ultimate result of PML-RAR action is to impose a heterochromatin-like structure on its target genes, thereby establishing a permanent transcriptional silencing. This effect is mediated by the previously described association of PML-RAR with chromatin-modifying enzymes (histone deacetylases and DNA methyltransferases) and by recruitment of the histone methyltransferase SUV39H1, responsible for trimethylation of lysine 9 of histone H3. [ABSTRACT FROM AUTHOR]

This article discusses a preliminary study on the feasibility of using an automatic algorithm to assess the likelihood of successful instrumental delivery in obstetrics. The algorithm analyzes ultrasound images to measure parameters such as the occiput position, head-perineum distance, and midline angle, and assigns a color code (green, yellow, or red) indicating the chances of success. The study found that the algorithm had a sensitivity of 0.80 and specificity of 0.82 for the green code, and a sensitivity of 0.64 and specificity of 0.80 for the yellow code. The authors conclude that these preliminary results are encouraging and suggest the potential for further improvements in clinical decision-making for delivery management. [Extracted from the article]

Acinar cystic transformation (ACT), also known as 'acinar cell cystadenoma', is an uncommon cystic neoplasm of pancreas with unknown malignant potential. This case regards a woman with symptomatic pancreatic head ACT, revealed with pathological exam of specimen after pancreaticoduodenectomy. A 57-years-old patient presented mild hyperbilirubinemia and recurrent cholangitis; she underwent to ERCP, EUS and MRI, and these exams revealed a large cyst of the pancreatic head that caused biliary compression. The discussion of the case by the multidisciplinary group indicated surgical resection. Pancreatic ACT is so rare, and its preoperative diagnosis is difficult. The symptoms of the patients and the features of the cyst are the criteria to choose a surgical resection. [ABSTRACT FROM AUTHOR]

Peaked density profiles are observed in FTU discharges when the recycling condition of the chamber is influenced by the action of the liquid lithium limiter (LLL) [1] . Turbulence analysis of lithium doped FTU plasmas [2,3] has shown that the presence of the light impurity modifies the phase between fluctuating fields responsible for transport and consequently leads to an inward deuterium pinch and outward impurity flux. Analogous peaked discharges were produced by Ne-gas puffing in different L mode plasma scenarios that have been recently obtained on FTU with following plasma parameters: I = 360 kA, B = 5–6.5 T, n e0 = 0.2–1 × 10 20 m −3 , T e0 = 1–4 keV, as well as in similar experiments on other machines [4] . In fact the Ne seeded plasmas show an increase of the peaking factor around 30% [5] . UV spectroscopy measurements confirm that the electron-density peaking arises from a convective flow and cannot be attributed to the contribution of the injected Ne alone. The Ne doped discharges analysis together with lithium conditioned ones is useful to extend the interpretative framework of the particle transport. In this work a comparison of the diffusion coefficient and of the pinch velocity of the two cases is conducted. By using a two-colors scanning interferometer providing very high spatial and time resolution, it is indeed possible to estimate the D and U coefficients of a simple model for the particle flux [6] . [ABSTRACT FROM AUTHOR]

Solid pseudopapillary tumour is a rare low-grade malignant potential carcinoma of the pancreas that typically occurs in females in their third decade. It most commonly occurs in the tail of the pancreas, although any site can be affected. Surgical resection is the standard treatment and offers an excellent prognosis. We report a case of a 17-year-old female with an acute onset abdominal pain and a radiological diagnosis of a cystic lesion in the distal pancreas. A robotic-assisted distal pancreatectomy with splenectomy was performed. Robotic-assisted surgery is an emerging technique for the treatment of pancreatic neoplasms. This approach can be considered for younger patients, thanks to the potential advantages of the robotic Da Vinci Xi System. [ABSTRACT FROM AUTHOR]

Abstract: Density profiles become broader, as the line averaged density is increased. At higher density, change of the trend is associated with the appearance of the MARFE. Lithium coated wall extends the maximum density accessible at low current (well above the Greenwald density limit) and can produce profiles with very high density gradient. At higher current the effect on the density limit can be exceeded only if the magnetic field is raised too. A comparison of successive similar discharges before and after wall conditioning with lithium showed a reduction of the MHD activity. [ABSTRACT FROM AUTHOR]

Recent efforts have succeeded in surveying open chromatin at the single-cell level, but high-throughput, single-cell assessment of heterochromatin and its underlying genomic determinants remains challenging. We engineered a hybrid transposase including the chromodomain (CD) of the heterochromatin protein-1α (HP-1α), which is involved in heterochromatin assembly and maintenance through its binding to trimethylation of the lysine 9 on histone 3 (H3K9me3), and developed a single-cell method, single-cell genome and epigenome by transposases sequencing (scGET-seq), that, unlike single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), comprehensively probes both open and closed chromatin and concomitantly records the underlying genomic sequences. We tested scGET-seq in cancer-derived organoids and human-derived xenograft (PDX) models and identified genetic events and plasticity-driven mechanisms contributing to cancer drug resistance. Next, building upon the differential enrichment of closed and open chromatin, we devised a method, Chromatin Velocity, that identifies the trajectories of epigenetic modifications at the single-cell level. Chromatin Velocity uncovered paths of epigenetic reorganization during stem cell reprogramming and identified key transcription factors driving these developmental processes. scGET-seq reveals the dynamics of genomic and epigenetic landscapes underlying any cellular processes. Single-cell mapping of heterochromatin and euchromatin using chromatin velocity defines trajectories of epigenetic modifications. [ABSTRACT FROM AUTHOR]

Lysine specific demethylase 1 KDM1A (LSD1) regulates histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time-resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC50, thus identifying four chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC50 = 2.9 μM) in complex with the enzyme. Initial expansion of this chemical class, both modifying core structure and decorating benzamide moiety, was directed toward the definition of the moieties responsible for the interaction with the enzyme. Preliminary optimization led to compound 90, which inhibited the enzyme with a submicromolar IC50 (0.162 μM), capable of inhibiting the target in cells. [ABSTRACT FROM AUTHOR]

The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described (Part 1, DOI 10.1021.acs.jmedchem.6b01018) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors. In particular, compounds 46, 49, and 50 showed single-digit nanomolar IC50 values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells, these compounds transcriptionally affected the expression of genes regulated by KDM1A such as CD14, CD11b, and CD86. Moreover, 49 and 50 showed a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells. [ABSTRACT FROM AUTHOR]

Aims: Vorinostat (suberoylanilide hydroxamic acid; SAHA) is a histone deacetylase inhibitor (HDACi) approved in the clinics for the treatment of T-cell lymphoma and with the potential to be effective also in breast cancer. We investigated the responsiveness to SAHA in human breast primary tumors and cancer cell lines. Results: We observed a differential response to drug treatment in both human breast primary tumors and cancer cell lines. Gene expression analysis of the breast cancer cell lines revealed that genes involved in cell adhesion and redox pathways, especially glutathione metabolism, were differentially expressed in the cell lines resistant to SAHA compared with the sensitive ones, indicating their possible association with drug resistance mechanisms. Notably, such an association was also observed in breast primary tumors. Indeed, addition of buthionine sulfoximine (BSO), a compound capable of depleting cellular glutathione, significantly enhanced the cytotoxicity of SAHA in both breast cancer cell lines and primary breast tumors. Innovation: We identify and validate transcriptional differences in genes involved in redox pathways, which include potential predictive markers of sensitivity to SAHA. Conclusion: In breast cancer, it could be relevant to evaluate the expression of antioxidant genes that may favor tumor resistance as a factor to consider for potential clinical application and treatment with epigenetic drugs (HDACis). Antioxid. Redox Signal. 23, 15-29. [ABSTRACT FROM AUTHOR]

The pure enantiomers of the N -(2-, 3-, and 4-(2-aminocyclopropyl)phenyl)benzamides hydrochlorides 11a – j were prepared and tested against LSD1 and MAO enzymes. The evaluation of the regioisomers 11a – j highlighted a net increase of the anti-LSD1 potency by shifting the benzamide moiety from ortho to meta and mainly to para position of tranylcypromine phenyl ring, independently from their trans or cis stereochemistry. In particular, the para -substituted 11a,b ( trans ) and 11g,h ( cis ) compounds displayed LSD1 and MAO-A inhibition at low nanomolar levels, while were less potent against MAO-B. The meta analogs 11c,d ( trans ) and 11i,j ( cis ) were in general less potent, but more efficient against MAO-A than against LSD1. In cellular assays, all the para and meta enantiomers were able to inhibit LSD1 by inducing Gfi-1b and ITGAM gene expression, with 11b , c and 11g – i giving the highest effects. Moreover, 11b and 11g,h strongly inhibited the clonogenic potential of murine promyelocytic blasts. [ABSTRACT FROM AUTHOR]

Since the 2010 IAEA-FEC Conference, FTU has exploited improvements in cleaning procedures and in the density control system to complete a systematic exploration of access to high-density conditions in a wide range of plasma currents and magnetic fields. The line-averaged densities at the disruptive limit increased more than linearly with the toroidal field, while no dependence on plasma current was found; in fact, the maximum density of 4.3 × 1020 m−3 was reached at B = 8 T even at the minimum current of 0.5 MA, corresponding to twice the Greenwald limit. The lack of plasma current dependence was due to the increase in density peaking with the safety factor. Experiments with the 140 GHz electron cyclotron resonance heating (ECRH) system were focused on the sawtooth (ST) period control and on the commissioning of a new launcher with real-time steering capability that will act as the front-end actuator of a real-time system for ST period control and tearing mode stabilization. Various ECRH and electron cyclotron current-drive modulation schemes were used; with the fastest one, the ST period synchronized with an 8 ms modulation period. The observed period variations were simulated using the JETTO code with a critical shear model for the crash trigger. The new launcher was of the plug-in type, allowing quick insertion and connection to the transmission line. Both beam characteristics and steering speed were in line with design expectation. Experimental results on the connection between improved coupling of lower hybrid waves in high-density plasmas and reduced wave spectral broadening were interpreted by fully kinetic, non-linear model calculations. A dual-frequency, time-of-flight diagnostic for the measurement of density profiles was developed and successfully tested. Fishbone-like instabilities driven by energetic electrons were simulated by the hybrid MHD-gyrokinetic XHMGC code. [ABSTRACT FROM AUTHOR]

One of the main problems in tokamak fusion devices concerns the capability to operate at a high plasma density, which is observed to be limited by the appearance of catastrophic events causing loss of plasma confinement. The commonly used empirical scaling law for the density limit is the Greenwald limit, predicting that the maximum achievable line-averaged density along a central chord depends only on the average plasma current density. However, the Greenwald density limit has been exceeded in tokamak experiments in the case of peaked density profiles, indicating that the edge density is the real parameter responsible for the density limit. Recently, it has been shown on the Frascati Tokamak Upgrade (FTU) that the Greenwald density limit is exceeded in gas-fuelled discharges with a high value of the edge safety factor. In order to understand this behaviour, dedicated density limit experiments were performed on FTU, in which the high density domain was explored in a wide range of values of plasma current (Ip = 500-900 kA) and toroidal magnetic field (BT = 4-8 T). These experiments confirm the edge nature of the density limit, as a Greenwald-like scaling holds for the maximum achievable line-averaged density along a peripheral chord passing at r/a ~ 4/5. On the other hand, the maximum achievable line-averaged density along a central chord does not depend on the average plasma current density and essentially depends on the toroidal magnetic field only. This behaviour is explained in terms of density profile peaking in the high density domain, with a peaking factor at the disruption depending on the edge safety factor. The possibility that the MARFE (multifaced asymmetric radiation from the edge) phenomenon is the cause of the peaking has been considered, with the MARFE believed to form a channel for the penetration of the neutral particles into deeper layers of the plasma. Finally, the magnetohydrodynamic (MHD) analysis has shown that also the central line-averaged density at the onset of the MHD activity depends only on the toroidal magnetic field. [ABSTRACT FROM AUTHOR]

The capability of predicting the density limit of a magnetically confined burning plasma is of crucial importance to establish the ultimate performance of a fusion power plant. The Greenwald density limit, commonly used as an empirical scaling law, predicts that the maximum achievable central line-averaged density is given by the relation nG = kJ, where J is the average plasma current density and k is the plasma elongation. However, several experiments have pointed out that such a limit can be overcome in the presence of peaked density profiles. This paper proposes a new empirical scaling law for a limiter tokamak operating in the low-energy confinement mode (L-mode) concerning the case of peaked density profiles associated with the presence of multifaceted asymmetric radiation from the edges. This result is based on dedicated experiments performed on the Frascati Tokamak Upgrade (FTU) under extremely clean machine conditions (Zeff = 1.0-1.5), in which the high-density domain is explored in a wide range of values of plasma current (Ip = 500-900 kA) and toroidal magnetic field (BT = 4-8 T). It is found that the maximum achievable central line-averaged density essentially depends on the toroidal magnetic field only and does not depend on the average plasma current density: the behaviour is explained in terms of density profile peaking in the high-density domain. As a confirmation that the limit is an edge limit, it is also shown that a Greenwald-like scaling (i.e. depending on the current density) actually holds for the edge line-averaged density (at r/a ≃ 4/5). [ABSTRACT FROM AUTHOR]

Abstract: Although epigenetic drugs have been approved for use in selected malignancies, there is significant need for a better understanding of their mechanism of action. Here, we study the action of a clinically approved DNA-methyltransferase inhibitor – decitabine (DAC) – in acute myeloid leukemia (AML) cells. At low doses, DAC treatment induced apoptosis of NB4 Acute Promyelocytic Leukemia (APL) cells, which was associated with the activation of the extrinsic apoptotic pathway. Expression studies of the members of the Death Receptor family demonstrated that DAC induces the expression of TNF-related apoptosis-inducing ligand (TRAIL). Upregulation of TRAIL, upon DAC treatment, was associated with specific epigenetic modifications induced by DAC in the proximity of the TRAIL promoter, as demonstrated by DNA demethylation, increased DNaseI sensitivity and histone acetylation of a non-CpG island, CpG-rich region located 2kb upstream to the transcription start site. Luciferase assay experiments showed that this region behave as a DNA methylation sensitive transcriptional regulatory element. The CpG regulatory element was also found methylated in samples derived from APL patients. These findings have been confirmed in the non-APL, AML Kasumi cell line, suggesting that this regulatory mechanism may be extended to other AMLs. Our study suggests that DNA methylation is a regulatory mechanism relevant for silencing of the TRAIL apoptotic pathway in leukemic cells, and further elucidates the mechanism by which epigenetic drugs mediate their anti-leukemic effects. [Copyright &y& Elsevier]

A new technique has been developed to produce plasmas with improved confinement relative to the H98,y2 scaling law (ITER Physics Expert Groups on Confinement and Transport and Confinement Modelling and Database ITER Physics Basics Editors and ITER EDA 1999 Nucl. Fusion 39 2175) on the JET tokamak. In the mid-size tokamaks ASDEX upgrade and DIII-D heating during the current formation is used to produce a flat q-profile with a minimum close to 1. On JET this technique leads to q-profiles with similar minimum q but opposite to the other tokamaks not to an improved confinement state. By changing the method utilizing a faster current ramp with temporary higher current than in the flattop (current overshoot) plasmas with improved confinement (H98,y2 = 1.35) and good stability (βN " 3) have been produced and extended to many confinement times only limited by technical constraints. The increase in H98,y2-factor is stronger with more heating power as can be seen in a power scan. The q-profile development during the high power phase in JET is reproduced by current diffusion calculated by TRANSP and CRONOS. Therefore the modifications produced by the current overshoot disappear quickly from the edge but the confinement improvement lasts longer, in some cases up to the end of the heating phase. [ABSTRACT FROM AUTHOR]

Protein acetylation is mediated by histone acetyltransferases (HATs) and deacetylases (HDACs), which influence chromatin dynamics, protein turnover and the DNA damage response. ATM and ATR mediate DNA damage checkpoints by sensing double-strand breaks and single-strand-DNA-RFA nucleofilaments, respectively. However, it is unclear how acetylation modulates the DNA damage response. Here we show that HDAC inhibition/ablation specifically counteracts yeast Mec1 (orthologue of human ATR) activation, double-strand-break processing and single-strand-DNA-RFA nucleofilament formation. Moreover, the recombination protein Sae2 (human CtIP) is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 and Rpd3, and one HAT, Gcn5, have key roles in these processes. We also find that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of hda1 and rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor, also causes Sae2 degradation. We propose that Rpd3, Hda1 and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand-break processing with autophagy. [ABSTRACT FROM AUTHOR]