Valproic acid induces apoptosis, p16INK4A upregulation and sensitization to chemotherapy in human melanoma cells.

It is known that melanoma develops as a consequence of multifactorial alterations. To date several studies indicate the effective implication of p16 as a tumor suppressor gene with a major role in either the development or progression of human melanoma. Deregulation of melanoma cell growth has been widely associated with mutations in the p16-cyclin D/cdk4-pRb pathway. Recently anticancer therapies are focused on restoration of p16 CDK inhibitory function and other proteins unregulated in melanoma cell cycle pathway (e.g., c-myc, p27). A combined strategy for restoration of normal homeostasis in the melanoma skin with targeted delivery of apoptosis-inducing agents does not seems to be far obtained. New class of antitumoral agents are emerging: histone deacetylase (HDAC) inhibitors have attracted much interest because of their ability to arrest cell growth, induce cell differentiation, and in some cases, induce apoptosis of cancer cells. Recently, attention has been focused on the ability of HDAC inhibitors to induce perturbation in cell cycle regulatory protein (e.g., p21(CIP1)) and down-regulation of survival signalling pathway. In the present study, we have examined the effect of valproic acid (VPA) on M14 human melanoma cell line. Here we observed that VPA induces cell cycle arrest and apoptosis sensitising melanoma cells to cis-platin and etoposide treatment. IC(50) dose (2.99 mM) of VPA was able to induce G(1) arrest (up to 75%) in association with upregulation of p16, p21 and cyclin-D1 related to Rb ipo-phosphorilation. In addition VPA activated apoptosis (50%) in M14 cells, when given alone or in combination with antitumoral agents. The ability of valproic acid to reestablished the G(1) pathway in melanoma cells suggests a potential application of VPA in melanoma therapeutic protocols

Prototyping industrial workstation in the Metaverse: a Low Cost Automation assembly use case

Low-cost Automation (LCA) represents a relevant use case that can benefit from a design and prototyping step experienced in Immersive Virtual Reality (IVR). LCA is a technology that automates some activities using mostly standard automation components available off-the-shelf. However, since LCA systems should adapt to existing standard production lines and workstations, workers need to customize standard LCA templates. This adaptation and customization step is usually performed on the real, physical LCA system, thus, it can be very time-consuming, and in case of errors it may be necessary to rebuild many parts from scratch. This paper investigates the usage of an Immersive Virtual Environment (IVE) as a tool for rapid and easy prototyping of LCA solutions. The proposed system loads from a digital library the 3D models of the components and provides users a set of tools to speed up the LCA system creation in a virtual room experienced through an IVR Headset. When the user completes the creation of the LCA system, it is possible to simulate its physical properties using the Unity 3D Physical Engine. Moreover, it is possible to obtain a list of all the pieces needed to build the prototype and their dimensions, to easily reproduce them in the real world. To assess the usability of the proposed system, a LCA building task has been defined, whereas users had to build a LCA solution using a template model for reference. Results show that the system usability has been highly appreciated by both skilled users and inexperienced ones

Key role of MEK/ERK pathway in sustaining tumorigenicity and in vitro radioresistance of embryonal rhabdomyosarcoma stem-like cell population

The identification of signaling pathways that affect the cancer stem-like phenotype may provide insights into therapeutic targets for combating embryonal rhabdomyosarcoma. The aim of this study was to investigate the role of the MEK/ERK pathway in controlling the cancer stem-like phenotype using a model of rhabdospheres derived from the embryonal rhabdomyosarcoma cell line (RD)

Association between a genetic variant of type-1 cannabinoid receptor and inflammatory neurodegeneration in multiple sclerosis

Genetic ablation of type-1 cannabinoid receptors (CB1Rs) exacerbates the neurodegenerative damage of experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS). To address the role on CB1Rs in the pathophysiology of human MS, we first investigated the impact of AAT trinucleotide short tandem repeat polymorphism of CNR1 gene on CB1R cell expression, and secondly on the inflammatory neurodegeneration process responsible for irreversible disability in MS patients. We found that MS patients with long AAT repeats within the CNR1 gene (≥12 in both alleles) had more pronounced neuronal degeneration in response to inflammatory white matter damage both in the optic nerve and in the cortex. Optical Coherence Tomography (OCT), in fact, showed more severe alterations of the retinal nerve fiber layer (RNFL) thickness and of the macular volume (MV) after an episode of optic neuritis in MS patients carrying the long AAT genotype of CNR1. MS patients with long AAT repeats also had magnetic resonance imaging (MRI) evidence of increased gray matter damage in response to inflammatory lesions of the white matter, especially in areas with a major role in cognition. In parallel, visual abilities evaluated at the low contrast acuity test, and cognitive performances were negatively influenced by the long AAT CNR1 genotype in our sample of MS patients. Our results demonstrate the biological relevance of the (AAT)n CNR1 repeats in the inflammatory neurodegenerative damage of MS

CNN-Based Approaches with Different Tumor Bounding Options for Lymph Node Status Prediction in Breast DCE-MRI

Background: The axillary lymph node status (ALNS) is one of the most important prognostic factors in breast cancer (BC) patients, and it is currently evaluated by invasive procedures. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), highlights the physiological and morphological characteristics of primary tumor tissue. Deep learning approaches (DL), such as convolutional neural networks (CNNs), are able to autonomously learn the set of features directly from images for a specific task. Materials and Methods: A total of 155 malignant BC lesions evaluated via DCE-MRI were included in the study. For each patient’s clinical data, the tumor histological and MRI characteristics and axillary lymph node status (ALNS) were assessed. LNS was considered to be the final label and dichotomized (LN+ (27 patients) vs. LN− (128 patients)). Based on the concept that peritumoral tissue contains valuable information about tumor aggressiveness, in this work, we analyze the contributions of six different tumor bounding options to predict the LNS using a CNN. These bounding boxes include a single fixed-size box (SFB), a single variable-size box (SVB), a single isotropic-size box (SIB), a single lesion variable-size box (SLVB), a single lesion isotropic-size box (SLIB), and a two-dimensional slice (2DS) option. According to the characteristics of the volumes considered as inputs, three different CNNs were investigated: the SFB-NET (for the SFB), the VB-NET (for the SVB, SIB, SLVB, and SLIB), and the 2DS-NET (for the 2DS). All the experiments were run in 10-fold cross-validation. The performance of each CNN was evaluated in terms of accuracy, sensitivity, specificity, the area under the ROC curve (AUC), and Cohen’s kappa coefficient (K). Results: The best accuracy and AUC are obtained by the 2DS-NET (78.63% and 77.86%, respectively). The 2DS-NET also showed the highest specificity, whilst the highest sensibility was attained by the VB-NET based on the SVB and SIB as bounding options. Conclusion: We have demonstrated that a selective inclusion of the DCE-MRI’s peritumoral tissue increases accuracy in the lymph node status prediction in BC patients using CNNs as a DL approach

Exploratory study on the associations between lifetime post-traumatic stress spectrum, sleep, and circadian rhythm parameters in patients with bipolar disorder

: The present study aimed at exploring whether lifetime post-traumatic stress spectrum symptoms are associated with chronotype in patients with bipolar disorder (BD). Moreover, we explored whether the chronotype can moderate the potential associations between lifetime post-traumatic stress spectrum symptoms and rest-activity circadian and sleep-related parameters. A total of 74 BD patients were administered the Trauma and Loss Spectrum Self-Report (TALS-SR) lifetime version for lifetime post-traumatic stress spectrum symptoms, the Pittsburgh Sleep Quality Index (PSQI) for self-reported sleep quality, and the Reduced Morningness-Eveningness Questionnaire (rMEQ) to discriminate evening chronotypes (ETs), neither chronotype (NT), and morning chronotype (MT). Actigraphic monitoring was used to objectively evaluate sleep and circadian parameters. Patients classified as ET reported significantly higher scores in the re-experiencing domain, as well as poorer sleep quality, lower sleep efficiency, increased wake after sleep onset, and delayed mid-sleep point compared with both NT and MT (p-value ≤ 0.05). Moreover, ET presented significantly higher scores in the TALS-SR maladaptive coping domain than NT and lower relative amplitude than MT (p-value ≤ 0.05). Moreover, higher TALS-SR total symptomatic domains scores were significantly correlated with poor self-reported sleep quality. Regression analyses showed that the PSQI score maintained the association with the TALS total symptomatic domains scores after adjusting for potentially confounding factors (age and sex) and that no interaction effect was observed between the chronotype and the PSQI. Conclusions: This exploratory study suggests that patients with BD classified as ET showed significantly higher lifetime post-traumatic stress spectrum symptoms and more disrupted sleep and circadian rhythmicity with respect to other chronotypes. Moreover, poorer self-reported sleep quality was significantly associated with lifetime post-traumatic stress spectrum symptoms. Further studies are required to confirm our results and to evaluate whether targeting sleep disturbances and eveningness can mitigate post-traumatic stress symptoms in BD

Multiple Acquired Mutations Captured by Liquid Biopsy in the EGFR Addicted Metastatic Colorectal Cancer.

Clinical Practice Points • Metastatic colorectal cancer is one of the most common causes of cancer death worldwide. • Primary and acquired resistance mechanisms to anti-EGFR treatment are a challenging topic with several clinical implications. • Primary resistance is defined by the presence of activating mutations in BRAF and RAS genes before treatment initiation, while acquired resistance refers to the selection of pre-existing mutant clones or de novo acquisition of mutations under the pressure of anti EGFR treatment. • Testing mutations in RAS and BRAF genes as predictive biomarkers is mandatory. • Liquid biopsy has acquired growing importance and showed to be reliable when compared to tissue NGS. • Liquid biopsy offers a full overview of the genetic landscape of the disease, overcoming spatial and temporal heterogeneity, when compared to tissue biopsy. • Liquid biopsy can be used to capture the changes in biology of cancer cells under the selective pressure of targeted agents over time. • Using complementary techniques allows to increase the diagnostic power and the biological significance of the results

Frailty Network in an Acute Care Setting: The New Perspective for Frail Older People

The incidence of elderly patients who come to the emergency room is progressively increasing. The specialization of the physician units might not be adequate for the evaluation of this complexity. The present study aimed to present a standard procedure, called ‘The Geriatric Frailty Network’, operating at the Policlinico Gemelli IRCCS Foundation, which is configured specifically for the level II assessment of frail elderly patients. This was a retrospective study in 1191 patients aged over 65, who were evaluated by the Geriatric Frailty Unit directly after emergency department admission for one year. All patients underwent multidimensional geriatric evaluation. Data were collected on demographics, co-morbidity, disease severity, and Clinical Frailty Scale. Among all patients, 723 were discharged directly from the emergency room with early identification of continuity of care path. Globally, 468 patients were hospitalized with an early assessment of frailty that facilitated the discharge process. The geriatric frailty network model aims to assist the emergency room and ward doctor in the prevention of the most common geriatric syndromes and reduce the number of incongruous hospitalization

Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: An open-label, 2 × 2 factorial, randomised phase 3 trial

Background: Whether addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel (EC-P) is favourable in adjuvant treatment of patients with node-positive breast cancer is controversial, as is the benefit of increased density of dosing. We aimed to address these questions in terms of improvements in disease-free survival. METHODS: In this 2 × 2 factorial, open-label, phase 3 trial, we enrolled patients aged 18-70 years with operable, node positive, early-stage breast cancer from 81 Italian centres. Eligible patients were randomly allocated in a 1:1:1:1 ratio with a centralised, interactive online system to receive either dose-dense chemotherapy (administered intravenously every 2 weeks with pegfilgrastim support) with fluorouracil plus EC-P (FEC-P) or EC-P or to receive standard-interval chemotherapy (administered intravenously every 3 weeks) with FEC-P or EC-P. The primary study endpoint was disease-free survival, assessed with the Kaplan-Meier method in the intention-to-treat population. Our primary comparisons were between dose schedule (every 2 weeks vs every 3 weeks) and dose type (FEC-P vs EC-P). This study is registered with ClinicalTrials.gov, number NCT00433420. FINDINGS: Between April 24, 2003, and July 3, 2006, we recruited 2091 patients. 88 patients were enrolled in centres that only provided standard-intensity dosing. After a median follow-up of 7·0 years (interquartile range [IQR] 4·5-6·3), 140 (26%) of 545 patients given EC-P every 3 weeks, 157 (29%) of 544 patients given FEC-P every 3 weeks, 111 (22%) of 502 patients given EC-P every 2 weeks, and 113 (23%) of 500 patients given FEC-P every 2 weeks had a disease-free survival event. For the dose-density comparison, disease-free survival at 5 years was 81% (95% CI 79-84) in patients treated every 2 weeks and 76% (74-79) in patients treated every 3 weeks (HR 0·77, 95% CI 0·65-0·92; p=0·004); overall survival rates at 5 years were 94% (93-96) and 89% (87-91; HR 0·65, 0·51-0·84; p=0·001) and for the chemotherapy-type comparison, disease-free survival at 5 years was 78% (75-81) in the FEC-P groups and 79% (76-82) in the EC-P groups (HR 1·06, 0·89-1·25; p=0·561); overall survival rates at 5 years were 91% (89-93) and 92% (90-94; 1·16, 0·91-1·46; p=0·234). Compared with 3 week dosing, chemotherapy every 2 weeks was associated with increased rate of grade 3-4 of anaemia (14 [1·4%] of 988 patients vs two [0·2%] of 984 patients; p=0·002); transaminitis (19 [1·9%] vs four [0·4%]; p=0·001), and myalgias (31 [3·1%] vs 16 [1·6%]; p=0·019), and decreased rates of grade 3-4 neutropenia (147 [14·9%] vs 433 [44·0%]; p<0·0001). Addition of fluorouracil led to increased rates of grade 3-4 neutropenia (354 [34·5%] of 1025 patients on FEC-P vs 250 [24·2%] of 1032 patients on EC-P; p<0·0001), fever (nine [0·9%] vs two [0·2%]), nausea (47 [4·6%] vs 28 [2·7%]), and vomiting (32 [3·1%] vs 15 [1·4%]). INTERPRETATION: In patients with node-positive early breast cancer, dose-dense adjuvant chemotherapy improved disease-free survival compared with standard interval chemotherapy. Addition of fluorouracil to a sequential EC-P regimen was not associated with an improved disease-free survival outcome