Exploring the potential of contrast agents in breast cancer echography: current state and future directions.

Breast cancer stands as the most frequent malignancy and leading cause of death among women. Early and accurate detection of this pathology represents a crucial factor in enhancing both incidence and mortality rates. Ultrasound (US) examination has been extensively adopted in clinical practice due to its non-invasiveness, affordability, ease of implementation, and wide accessibility, thus representing a valuable first-line diagnostic tool for the study of the mammary gland. In this scenario, recent developments in nanomedicine are paving the way for new interpretations and applications of US diagnostics, which are becoming increasingly personalized based on the molecular phenotype of each tumor, allowing for more precise and accurate evaluations. This review highlights the current state-of-the-art of US diagnosis of breast cancer, as well as the recent advancements related to the application of US contrast agents to the field of molecular diagnostics, still under preclinical study.

Suicidality in a psychiatric inpatient unit: a 2-year retrospective study in Umbria, central Italy.

Suicide ranks among the 10 leading causes of death worldwide; in Italy, almost 4000 persons per year die by suicide. Studies focusing on suicidality in Italian inpatient samples before the COVID-19 pandemic are scant. We, thus, aimed to define sociodemographic and clinical variables associated with suicidal ideation (SI) and deliberate self-harm (DSH) in a sample of inpatients admitted to a Psychiatric Inpatient Unit. This retrospective study was conducted in the Psychiatric Inpatient Unit of the Perugia Hospital, from January 2018 to December 2019. Sociodemographic and clinical characteristics, including diagnostic and treatment features, were collected from the medical records of subjects admitted for suicidality-related phenomena, namely DSH and SI. The prevalence of suicidality-related phenomena in the sample ( n = 850) was 14.12% (n=120) and was mainly due to DSH ( n = 84; 70%). Subjects hospitalized due to these conditions were more frequently females, separated, and displayed a higher prevalence of personality disorders, especially borderline personality disorder. People in the suicidality-related phenomena subgroup were more often committed involuntarily and reported multiple hospitalizations less frequently than other inpatients. They were receiving community treatment in a higher percentage of cases, and lithium was prescribed more frequently than among inpatients who were hospitalized for reasons other than suicidality. Our study provides a further characterization of psychiatric inpatients who experience SI or perform DSH. Targeted treatment strategies should be considered for subjects suffering from personality disorders who experience suicidality-related phenomena.

Psychiatric Comorbidity in Bariatric Surgery: A Retrospective Study in a General Hospital.

BACKGROUND: Candidates for bariatric surgery undergo a multidisciplinary evaluation in the pre-operative phase, including a psychiatric visit aimed at the screening for psychiatric comorbidities, including feeding and eating disorders (FEDs), which are shortcomings to the intervention or predictors of worse prognosis. The presence of FEDs, such as Binge Eating Disorder (BED) and Bulimia Nervosa (BN), is associated with higher rates of other psychiatric disorders. Furthermore, there is evidence of the association between obesity and Depressive Disorders, as well as B and C Cluster Personality Disorders. The aim of this study was to evaluate the presence of psychiatric comorbidities among a population of candidates for bariatric surgery. SUBJECTS AND METHODS: Subjects were recruited at the outpatient service of the Section of Psychiatry, Clinical Psychology and Rehabilitation of the General Hospital/University of Perugia after being referred by surgeons. Psychiatric comorbidities were investigated by means of the Structured Clinical Interview for DSM-5 Disorders. Subjects underwent specific assessment with scales for the evaluation of FEDs, namely Binge Eating Scale, Obesity Questionnaire, Bulimia Test-Revised and Body Shape Questionnaire. RESULTS: The sample consisted of 101 subjects: 43 (42.6%) were diagnosed with at least one psychiatric disorder, including FEDs. In particular, 30 subjects (29.7%) presented at least one FED, among which the most frequent were FED not otherwise specified (24.1%) and BED (6.8%). Moreover, 26 subjects (25.7%) were diagnosed with at least one psychiatric disorder other than FEDs, such as Personality Disorders (17.1%), with a higher prevalence of B and C Cluster Disorders. Depressive Disorders were detected in 5% of the sample. CONCLUSIONS: Subjects undergoing bariatric surgery often display psychiatric comorbidities, more frequently one or more FEDs. The systematic screening of these conditions should be implemented in the clinical practice in order to provide early intervention strategies and adequate monitoring.

Antepartum Distress during COVID-19 Pandemic: an Observational Study.

BACKGROUND: The present study investigates the impact of the Coronavirus diseases 2019 (Covid-19) pandemic on the subjective experience of pregnant women, as well as the impact of the pandemic on this population in terms of psychopathological correlates. SUBJECTS AND METHODS: Pregnant women referring to the Section of Obstetrics and Gynecology of the General Hospital of Perugia, Italy, were recruited from 1st May, 2021 to 15th June, 2021. Socio-demographic and clinical data was collected, as well as information regarding the Covid-19 pandemic impact on the subjective experience of pregnancy. Psychopathology was evaluated by means of the State-Trait Anxiety Inventory Form Y (STAI-Y), the Symptom Checklist-90 (SCL-90) and the Prenatal Distress Measure (Pre-DM). Descriptive analyses were performed. Significant associations between distress symptoms and the collected sociodemographic and clinical variables were assessed by using the Pearson correlation (p<0.05). RESULTS: 25 women were included in the study. Among these, 18 (72%) reported that the Covid-19 pandemic negatively impacted their experience of pregnancy. Were detected an average Pre-DM total score of 7.28±4.33 and an average state anxiety scale value of 35.56±9.21 and an average trait anxiety scale value of 34.04±7.44 at the STAI-Y. A global severity index > 1 at SCL-90 was detected in 8.3% of the sample. CONCLUSIONS: The identification of antepartum distress and the early treatment of perinatal psychopathology represent a priority during the Covid-19 pandemic era.

Suicidality and COVID-19: Data from an Emergency Setting in Italy.

BACKGROUND: Suicidality is a widespread phenomenon with a dramatic burden worldwide. The Coronavirus disease 2019 (Covid-19) pandemic determined a relevant impact on mental health, due to the infection itself and its socio-economic consequences. The present study is aimed at analyzing the prevalence of suicidality during the Covid-19 pandemic among subjects requiring a psychiatric consultation in an emergency setting. SUBJECTS AND METHODS: Socio-demographic and clinical information was collected at the emergency department of the General Hospital of Perugia from June 1st, 2020 to January 31st, 2021. Data was entered into an electronic datasheet and retrospectively analysed. Pearson's bivariate correlation was performed in order to assess significant associations between suicide-related variables and specific socio-demographic and clinical features (p<0.05). RESULTS: Among 447 subjects included in the analysis, 109 (24.4%) showed suicidality-related phenomena, particularly suicide attempts (SA) (n=44, 9.8%), suicidal ideation (SI) (n=41, 9.2%), non suicidal self-injury (NSSI) (n=31, 6.9%), that in some cases co-occurred. A statistically significant association was detected between NSSI and living with marital family (p=0.024) and between suicidality-related phenomena and adjustment disorders (p=0.018). None of the examined subjects reported a previous positivity for Covid-19 and neither did their relatives. CONCLUSIONS: The present study confirms the impact of the Covid-19 pandemic on suicide-related phenomena. Consultation psychiatry fulfills a key role in the early detection and clinical management of these conditions, that require targeted intervention strategies.

Accuracy of ADC ratio in discriminating true and false positives in multiparametric prostatic MRI.

PURPOSE: Our goal was to evaluate the usefulness of apparent diffusion coefficient (ADC) ratios in discriminating true from false positives in multiparametric (mp) prostate MRI in clinical practice. METHODS: We retrospectively evaluated 98 prostate lesions in a series of 73 patients who had undergone prostate mpMRI and standard 12-core prostatic biopsy in our institution from 2016 to 2018. Two experienced radiologists performed double blind ADC value quantifications of both MRI-identified lesions and apparently benign contralateral prostatic parenchyma in a circular region of interest (ROI) of ∼10 mm2. The ratios between the mean values of both measurements (i.e., ADC ratio mean) and between the minimum value of the lesion and the maximum value of the benign parenchyma (i.e., ADC ratio min-max) were automatically calculated. The malignancy of all lesions was determined through biopsy according to Gleason score (GS ≥ 6) and localization. RESULTS: For Reader 1, the area under the ROC curve (AUC) of ADC ratio mean and ADC ratio min-max were 0.72 and 0.67, respectively, whereas for Reader 2 these values were 0.74 and 0.71, respectively. The best cut-off values for ADC ratio means were ≥ 0.5 (Reader 1) and ≥ 0.6 (Reader 2), with a sensitivity of 76.3 % and 84.2 % and a specificity of 51.7 % and 50 %, respectively. Moreover, based on a threshold of 0.6, no clinically significant prostate cancer (csPCa) was missed by Reader 1, while only one went unnoticed by Reader 2. CONCLUSION: The ADC ratio is a useful and moderately accurate complementary tool to diagnose prostate cancer in the mp-MRI.

Selectivity of the CUBAN domain in the recognition of ubiquitin and NEDD8.

Among the members of the ubiquitin-like (Ubl) protein family, neural precursor cell expressed developmentally down-regulated protein 8 (NEDD8) is the closest in sequence to ubiquitin (57% identity). The two modification mechanisms and their functions, however, are highly distinct and the two Ubls are not interchangeable. A complex network of interactions between modifying enzymes and adaptors, most of which are specific while others are promiscuous, ensures selectivity. Many domains that bind the ubiquitin hydrophobic patch also bind NEDD8 while no domain that specifically binds NEDD8 has yet been described. Here, we report an unbiased selection of domains that bind ubiquitin and/or NEDD8 and we characterize their specificity/promiscuity. Many ubiquitin-binding domains bind ubiquitin preferentially and, to a lesser extent, NEDD8. In a few cases, the affinity of these domains for NEDD8 can be increased by substituting the alanine at position 72 with arginine, as in ubiquitin. We have also identified a unique domain, mapping to the carboxyl end of the protein KHNYN, which has a stark preference for NEDD8. Given its ability to bind neddylated cullins, we have named this domain CUBAN (Cullin-Binding domain Associating with NEDD8). We present here the solution structure of the CUBAN domain both in the isolated form and in complex with NEDD8. The results contribute to the understanding of the discrimination mechanism between ubiquitin and the Ubl. They also provide new insights on the biological role of a ill-defined protein, whose function is hitherto only predicted.

One year in review 2018: Sjögren's syndrome.

Sjögren's syndrome is a complex and potentially disabling slow progressive, systemic disorder. During the last twelve months several original and important contributions have been published on the pathogenesis, diagnosis and therapy of the disease. This review, following the others of this series is aimed at summarising some of the most significant studies that have been recently published. Regarding the pathogenesis, we will specifically focus on novel insights on miRNA, gut microbiota, adaptive and innate autoimmunity and animal models. Concerning novelties in pSS diagnosis, we will focus on salivary gland ultrasonography and histology. Finally, we will conclude with an update of the clinical manifestations of the disease and with an overview of the future therapies.

Discrepancy between subjective symptoms, objective measures and disease activity indexes: the lesson of primary Sjögren's syndrome.

Mucosal dryness is a key clinical feature in primary Sjögren's syndrome (pSS) and its assessment relies on both objective measurement of residual secretion and subjective symptoms reported by patients. However, while the objective assessment and grading of glandular dysfunction can be easily performed, the spectrum of clinical symptoms encompassed by the terms 'dry eye' and 'dry mouth' is wide and heterogeneous. Therefore, patient reported outcomes (PROs) for dryness in pSS poorly correlate with the amount of glandular secretion. In addition, subjective dryness is not correlated with the severity of systemic disease and severely affects the patient quality of life even in presence of active extraglandular manifestations. The purpose of this review article is to provide an overview of glandular dysfunction in pSS as well as the impact of discrepancy between objective assessment, subjective symptom and extraglandular disease activity on disease management.

The prevalence and relevance of traditional cardiovascular risk factors in primary Sjögren's syndrome.

Accelerated atherosclerosis is a distinct feature of some inflammatory and autoimmune disorders and several specific autoimmune mechanisms and persistent inflammation have been identified to exert a pivotal role in precocious atherosclerotic damage in these disorders. Although increased atherosclerotic risk has been well established in some rheumatic autoimmune systemic diseases, such as systemic lupus erythematosus and rheumatoid arthritis, reliable data regarding the prevalence and pathogenetic mechanisms associated with increased atherosclerotic damage in primary Sjögren's syndrome are scarse. Indeed, primary Sjögren's syndrome is an autoimmune disorder characterised by chronic inflammation and autoimmune dysregulation that shares many pathogenic mechanisms and clinical features with systemic lupus erythematosus and rheumatoid arthitis. Higher prevalence of subclinical atherosclerosis has been observed in primary Sjögren's syndrome patients and recent population-based studies demonstrated an increased risk of cardiovascular events in these patients in comparison to general population. Among mechanisms associated with atherosclerotic damage, the prevalence and the role of traditional cardiovascular risk factors have been poorly investigated. In particular, the issue of whether the presence of these cardiovascular risk factors is associated with an increased risk of cardiovascular events needs to be further explored.

Targeting Inflammation to Prevent Cardiovascular Disease in Chronic Rheumatic Diseases: Myth or Reality?

Evidence for increased risk of cardiovascular morbidity and mortality in chronic inflammatory rheumatic diseases has accumulated during the last years. Traditional cardiovascular risk factors contribute in part to the excess of cardiovascular risk in these patients and several mechanisms, including precocious acceleration of subclinical atherosclerotic damage, inflammation, and immune system deregulation factors, have been demonstrated to strictly interplay in the induction and progression of atherosclerosis. In this setting, chronic inflammation is a cornerstone of rheumatic disease pathogenesis and exerts also a pivotal role in all stages of atherosclerotic damage. The strict link between inflammation and atherosclerosis suggests that cardiovascular risk may be reduced by rheumatic disease activity control. There are data to suggest that biologic therapies, in particular TNFα antagonists, may improve surrogate markers of cardiovascular disease and reduce CV adverse outcome. Thus, abrogation of inflammation is considered an important outcome for achieving not only control of rheumatic disease, but also reduction of cardiovascular risk. However, the actual effect of anti-rheumatic therapies on atherosclerosis progression and CV outcome in these patients is rather uncertain due to great literature inconsistency. In this paper, we will summarize some of the main mechanisms linking the inflammatory pathogenic background underlying rheumatic diseases and the vascular damage observed in these patients, with a particular emphasis on the pathways targeted by currently available therapies. Moreover, we will analyze current evidence on the potential atheroprotective effects of these treatments on cardiovascular outcome pointing out still unresolved questions.

One year in review 2017: systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that predominately affects women. It is characterised by a broad spectrum of clinical manifestations, however, its course and organ involvement are unpredictable. Although over the last few decades an improvement in survival for SLE patients has been observed, pathogenic mechanisms underlying this disease are still unclear. Comorbidities, due to both disease and treatment, as well as multiple aspects of SLE, are under intensive investigation. Following the previous annual reviews of this series, we hereby provide a critical digest of the recent papers on SLE focusing on pathogenesis, clinical and laboratory features, as well as current and new therapeutic strategies published over the last year.

One year in review 2016: systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a highly variable course and prognosis. The management of the disease is still a clinical challenge for the treating physicians as many aspects regarding the disease pathogenesis, clinical picture and outcomes remain to be elucidated. New and interesting data are emerging; here the recent literature on SLE pathogenesis, clinical and laboratory aspects, as well as treatments and comorbidities, are reviewed and the main findings summarised in order to provide a bird's eye on the relevant papers on these topics.

Myosin VI Contains a Compact Structural Motif that Binds to Ubiquitin Chains.

Myosin VI is critical for cargo trafficking and sorting during early endocytosis and autophagosome maturation, and abnormalities in these processes are linked to cancers, neurodegeneration, deafness, and hypertropic cardiomyopathy. We identify a structured domain in myosin VI, myosin VI ubiquitin-binding domain (MyUb), that binds to ubiquitin chains, especially those linked via K63, K11, and K29. Herein, we solve the solution structure of MyUb and MyUb:K63-linked diubiquitin. MyUb folds as a compact helix-turn-helix-like motif and nestles between the ubiquitins of K63-linked diubiquitin, interacting with distinct surfaces of each. A nine-amino-acid extension at the C-terminal helix (Helix2) of MyUb is required for myosin VI interaction with endocytic and autophagic adaptors. Structure-guided mutations revealed that a functional MyUb is necessary for optineurin interaction. In addition, we found that an isoform-specific helix restricts MyUb binding to ubiquitin chains. This work provides fundamental insights into myosin VI interaction with ubiquitinated cargo and functional adaptors.

One year in review: the pathogenesis of rheumatoid arthritis.

The pathogenesis of rheumatoid arthritis (RA) is a complex scenario that, to date, is not fully elucidated. However, scientific progress has enabled us to understand several mechanisms underlying the development of the disease. The breakdown of self-tolerance in genetically predisposed individuals and the aberrant activation of innate and adaptive immune responses culminate in synovial hyperplasia and bone destruction. In addition, extra-articular manifestations, as well as the burden of increased cardiovascular risk (CVR), in patients with RA represent another interesting aspect of RA pathogenesis under intense investigation. The purpose of this review article is to provide an overview of the new insights in RA pathogenesis summarising the most relevant studies published over the last year.

Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming.

Homologous to E6-AP C terminus (HECT) E3 ligases recognize and directly catalyze ligation of ubiquitin (Ub) to their substrates. Molecular details of this process remain unknown. We report the first structure, to our knowledge, of a Ub-loaded E3, the human neural precursor cell-expressed developmentally downregulated protein 4 (Nedd4). The HECT(Nedd4)~Ub transitory intermediate provides a structural basis for the proposed sequential addition mechanism. The donor Ub, transferred from the E2, is bound to the Nedd4 C lobe with its C-terminal tail locked in an extended conformation, primed for catalysis. We provide evidence that the Nedd4-family members are Lys63-specific enzymes whose catalysis is mediated by an essential C-terminal acidic residue.

Structure of the HECT:ubiquitin complex and its role in ubiquitin chain elongation.

Several mechanisms have been proposed for the synthesis of substrate-linked ubiquitin chains. HECT ligases directly catalyse protein ubiquitination and have been found to non-covalently interact with ubiquitin. We report crystal structures of the Nedd4 HECT domain, alone and in complex with ubiquitin, which show a new binding mode involving two surfaces on ubiquitin and both subdomains of the HECT N-lobe. The structures suggest a model for HECT-to-substrate ubiquitin transfer, in which the growing chain on the substrate is kept close to the catalytic cysteine to promote processivity. Mutational analysis highlights differences between the processes of substrate polyubiquitination and self-ubiquitination.