e23522 Background: Malignant phyllodes tumors of the breast (B-MPT) are supposed to arise de novo or to derive from a fibroadenoma/benign phyllodes tumor ("secondary"), through a MED12-dependent ...pathway. Secondary B-MPTs may be associated to better outcomes: both the history of previous fibroadenomas and the presence of MED12 mutations were demonstrated to be associated to improved recurrence-free survival, in small case series. We assessed the prevalence and the prognostic value of fibroadenoma-like areas (FLA) in the context of B-MPTs, which were described as potentially associated with MED12 mutations (Pareja, 2017). Methods: Single-center, retrospective, translational study conducted at European Institute of Oncology. Consecutive patients aged 18 years old or more, with non-metastatic B-MPT, who underwent surgery from Jan 2000 to Dec 2021, were included. FLA were defined as intracanalicular, pericanalicular or myxoid areas of low stromal cellularity, lacking cytologic atypia and mitotic activity. All specimens were reviewed by three pathologists. The endpoints were the cumulative incidences of distant and local recurrences. Results: 89 patients were included (Table). After a median follow-up of 6.4 years, 18 and 14 local and distant recurrences were registered, respectively. The cumulative incidences at 5-years of local and distant recurrences were 19% (95% Confidence Interval CI, 11–28%) and 11% (95%CI, 5–18%). 47% of tumors had FLA, which were associated with lower ( < 15/10HPF) mitoses (p = 0.05). No pathologic feature was associated with distant or local relapse. The presence of FLA areas was associated with fewer local recurrences, without reaching the statistical significance (p = 0.14); no difference in terms of distant recurrences emerged (p = 0.61). Conclusions: 47% of B-MPTs are characterized by FLAs, which are associated with a lower mitotic count. The association between FLAs and fewer local recurrences did not reach the threshold for statistical significance, probably due to the small number of events. The prognostic role of FLAs needs to be assessed in a larger cohort and may potentially enhance the selection of patients deserving postoperative treatment intensification. Table: see text
Fractal Dimension (FD) has shown to be a promising means to describe the morphology of cortical structures across different neurologic and psychiatric conditions, displaying a good sensitivity in ...capturing atrophy processes. In this study, we aimed at exploring the morphology of cortical areas by means of FD in 58 female patients with Anorexia Nervosa (AN) (38 currently underweight and 20 fully recovered) and 38 healthy controls (HC). All participants underwent high-resolution MRI. Surface extraction was completed using FreeSurfer, FD was computed using the calcFD toolbox. The whole cortex mean FD value was lower in acute AN patients compared to HC (
< 0.001). Recovered AN patients did not show differences in the global FD when compared to HC. However, some brain areas showed higher FD in patients than controls, while others showed the opposite pattern. Parietal regions showed lower FD in both AN groups. In acute AN patients, the FD correlated with age (
< 0.001), body mass index (
= 0.019) and duration of illness (
= 0.011). FD seems to represent a feasible method to explore cortical complexity in patients with AN since it demonstrated to be sensitive to the effects of both severity and duration of malnutrition.
•HCB stimulates the angiogenic switch, increasing VEGF expression in a xenograft model.•HCB enhances VEGFR2 expression, and activates its downstream pathways in HMEC-1.•HCB induces COX-2 and VEGF ...expression protein levels in AhR-dependent manner in HMEC-1.•HCB increases HMEC-1 migration and neovasculogenesis involving AhR, COX-2 and VEGFR2.
Exposure to environmental pollutants may alter proangiogenic ability and promotes tumor growth. Hexachlorobenzene (HCB) is an organochlorine pesticide found in maternal milk and in lipid foods, and a weak ligand of the aryl hydrocarbon receptor (AhR). HCB induces migration and invasion in human breast cancer cells, as well as tumor growth and metastasis in vivo. In this study, we examined HCB action on angiogenesis in mammary carcinogenesis. HCB stimulates angiogenesis and increases vascular endothelial growth factor (VEGF) expression in a xenograft model with the human breast cancer cell line MDA-MB-231. Human microvascular endothelial cells HMEC-1 exposed to HCB (0.005, 0.05, 0.5 and 5μM) showed an increase in cyclooxygenase-2 (COX-2) and VEGF protein expression involving AhR. In addition, we found that HCB enhances VEGF-Receptor 2 (VEGFR2) expression, and activates its downstream pathways p38 and ERK1/2. HCB induces cell migration and neovasculogenesis in a dose-dependent manner. Cells pretreatment with AhR, COX-2 and VEGFR2 selective inhibitors, suppressed these effects. In conclusion, our results show that HCB promotes angiogenesis in vivo and in vitro. HCB-induced cell migration and tubulogenesis are mediated by AhR, COX-2 and VEGFR2 in HMEC-1. These findings may help to understand the association among HCB exposure, angiogenesis and mammary carcinogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Hereditary transthyretin amyloidosis (ATTRv, v for variant) prevalence in Italy, a non-endemic region, has been established by ATTRv amyloidosis Italian Registry. However, values of prevalence were ...extremely heterogeneous, considering different regions. To properly establish the prevalence of the disease in the Lazio region, a survey was sent to university regional hospitals and to main regional hospitals, in order to collect all affected patients regularly followed. We identified 100 ATTRv patients and, considering a Lazio population of 5.8/million, we estimated a ATTRv prevalence of 17.2/million. The ATTRv amyloidosis Italian Registry reported a prevalence of 8.0/million in Lazio, while our survey showed a value of double this. Our survey documented a high-prevalence for a non-endemic country. The increased awareness of the disease among general practitioners and medical specialists is a fundamental step to reduce the diagnostic delay and start an effective treatment of this disease.
Silicon is usually considered a brittle material. However, under specific conditions, such as high temperature, high confining pressure, and complex loading patterns involved in surface machining or ...microindentation, extremely localized regions with plastic deformation may show up. Herein this paper, we demonstrate the possibility to induce a permanent deformation field extending over macroscopically wide regions, with no need for extreme load. Indeed, this is obtained at room temperature upon applying a relatively small pressure onto single crystal silicon slices machined with a pre-notch at the bottom surface. To deeply characterize the deformed region, which is visible to the naked eye, we adopted an experimental multiscale approach, which involves a combination of optical microscopy and profilometry, Raman spectroscopy, and Electron Backscatter Diffraction (EBSD). Overall, the results collected via different techniques show, in a consistent fashion, that our proposed methodology is an effective engineering pathway to induce controlled permanent deformation in silicon samples, whose effects can be observed across different length scales, from macro to nano.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The bank vole is a rodent susceptible to different prion strains from humans and various animal species. We analyzed the transmission features of different prions in a panel of seven rodent species ...which showed various degrees of phylogenetic affinity and specific prion protein (PrP) sequence divergences in order to investigate the basis of vole susceptibility in comparison to other rodent models. At first, we found a differential susceptibility of bank and field voles compared to C57Bl/6 and wood mice. Voles showed high susceptibility to sheep scrapie but were resistant to bovine spongiform encephalopathy, whereas C57Bl/6 and wood mice displayed opposite features. Infection with mouse-adapted scrapie 139A was faster in voles than in C57Bl/6 and wood mice. Moreover, a glycoprofile change was observed in voles, which was reverted upon back passage to mice. All strains replicated much faster in voles than in mice after adapting to the new species. PrP sequence comparison indicated a correlation between the transmission patterns and amino acids at positions 154 and 169 (Y and S in mice, N and N in voles). This correlation was confirmed when inoculating three additional rodent species: gerbils, spiny mice and oldfield mice with sheep scrapie and 139A. These rodents were chosen because oldfield mice do have the 154N and 169N substitutions, whereas gerbil and spiny mice do not have them. Our results suggest that PrP residues 154 and 169 drive the susceptibility, molecular phenotype and replication rate of prion strains in rodents. This might have implications for the assessment of host range and molecular traceability of prion strains, as well as for the development of improved animal models for prion diseases.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•TRD is a significant health burden, aiming for personalized interventions.•Machine learning approaches may improve precision of treatment strategies.•We trained ML models to predict Esketamine Nasal ...Spray response in TRD subjects.•Anhedonia, anxious distress and mixed features increase probability of response/remission.•Benzodiazepine use and depression severity may delay treatment response.
Treatment-resistant depression (TRD) represents a severe clinical condition with high social and economic costs. Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD by EMA and FDA, but data about predictors of response are still lacking. Thus, a tool that can predict the individual patients’ probability of response to ESK-NS is needed.
This study investigates sociodemographic and clinical features predicting responses to ESK-NS in TRD patients using machine learning techniques. In a retrospective, multicentric, real-world study involving 149 TRD subjects, psychometric data (Montgomery-Asberg-Depression-Rating-Scale/MADRS, Brief-Psychiatric-Rating-Scale/BPRS, Hamilton-Anxiety-Rating-Scale/HAM-A, Hamilton-Depression-Rating-Scale/HAMD-17) were collected at baseline and at one month/T1 and three months/T2 post-treatment initiation. We trained three different random forest classifiers, able to predict responses to ESK-NS with accuracies of 68.53% at T1 and 66.26% at T2 and remission at T2 with 68.60% of accuracy. Features like severe anhedonia, anxious distress, mixed symptoms as well as bipolarity were found to positively predict response and remission. At the same time, benzodiazepine usage and depression severity were linked to delayed responses. Despite some limitations (i.e., retrospective study, lack of biomarkers, lack of a correct interrater-reliability across the different centers), these findings suggest the potential of machine learning in personalized intervention for TRD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background
Treatment-resistant depression (TRD) is defined by the European Medicines Agency as a lack of clinically meaningful improvement after treatment, with at least two different ...antidepressants. Individual, familiar, and socio-economic burden of TRD is huge. Given the lack of clear guidelines, the large variability of TRD approaches across different countries and the availability of new medications to meet the need of effective and rapid acting therapeutic strategies, it is important to understand the consensus regarding the clinical characteristics and treatment pathways of patients with TRD in Italian routine clinical practice, particularly in view of the recent availability of esketamine nasal spray.
Methods
A Delphi questionnaire with 17 statements (with a 7 points Likert scale for agreement) was administered via a customized web-based platform to Italian psychiatrists with at least 5 years of experience and specific expertise in the field of depression. In the second-round physicians were asked to answer the same statements considering the interquartile range of each question as an index of their colleagues’ responses. Stata 16.1 software was used for the analyses.
Results
Sixty panellists, representative of the Italian territory, answered the questionnaire at the first round. For 8/17 statements more than 75% of panellists reached agreement and a high consensus as they assigned similar scores; for 4 statements the panellists assigned similar scores but in the middle of the Likert scale showing a moderate agreement with the statement, while for 5 statements there was indecision in the agreement and low consensus with the statement.
Conclusions
This Delphi Panel showed that there is a wide heterogeneity in Italy in the management of TRD patients, and a compelling need of standardised strategies and treatments specifically approved for TRD. A high level of consensus and agreement was obtained about the importance of adding lithium and/or antipsychotics as augmentation therapies and in the meantime about the need for long-term maintenance therapy. A high level of consensus and agreement was equally reached for the identification of esketamine nasal spray as the best option for TRD patients and for the possibility to administrate without difficulties esketamine in a community outpatient setting, highlighting the benefit of an appropriate educational support for patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
One hundred and four scrapie positive and 77 negative goats from 34 Greek mixed flocks were analysed by prion protein gene sequencing and 17 caprine scrapie isolates from 11 flocks were submitted to ...molecular isolate typing. For the first time, the protective S146 variant was reported in Greece, while the protective K222 variant was detected in negative but also in five scrapie positive goats from heavily infected flocks. By immunoblotting six isolates, including two goat flockmates carrying the K222 variant, showed molecular features slightly different from all other Greek and Italian isolates co-analysed, possibly suggesting the presence of different scrapie strains in Greece.
Classical scrapie is a contagious prion disease of sheep and goats. It is endemic in many countries in Europe, North America, and Asia. In Africa, imported scrapie cases have been described in South ...Africa and Kenia in the past. More recently, several cases have been reported from different regions of Libya, based on clinical signs and histological lesions. Here, we report the results of thorough investigations carried out on a suspect case of scrapie in a 6-year-old Barbarine sheep, born, and bred in Tunisia, showing behavioral changes, weight loss, itching, skin lesions, wool loss, and motor incoordination. Histopathology and immunohistochemistry revealed spongiform change in several brain areas with associated pathological prion protein deposition. Western blotting confirmed the diagnosis and showed a classical scrapie-like molecular pattern of PrPres, different from atypical scrapie and bovine spongiform encephalopathy (BSE) in small ruminants. Sequence analysis of the prion protein gene showed that the animal carried the ARQ/ARQ genotype, one of the most susceptible to classical scrapie. The inoculation of sheep brain homogenate in a susceptible rodent model proved the experimental transmissibility of the disease. These results demonstrate the circulation of classical scrapie in Tunisia and confirm its presence in North Africa, indicating the need to improve epidemiological surveillance and diagnostic capacity for prion diseases in the region.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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