An Italian observational study on subclinical cardiovascular risk factors and depressive symptomatology. A suggestion for the potential utility of a sinergic cardio-psychiatric perspective

Introduction Growing evidence has been collected over the complex, intertwined pathophysiological connection among subclinical cardiovascular (CV) disease, i.e. atherosclerosis, systemic low pro-inflammatory states and psychiatric disorders/symptomatology (anxiety, depression), with controversial results. Aim Aim of this study was to investigate the possible link between subclinical CV risk factors (atherosclerosis), depressive symptoms, and inflammation. Methods Cross-sectional study. Inclusion criteria: outpatients aged ≥40 years, attending colonoscopy after positive faecal occult blood test, negative medical history for cancer. Collected data: blood pressure, glycaemia, lipid profile, waist circumference, BMI, PCR (C reactive protein), LPS (bacterial lipopolysaccharide), ultrasound carotid intima-media thickness (c-IMT). Psychometric tests: HADS, TCI, IMSA, SF36. Statistical analysis performed with STATA13. Results The 54 patients enrolled were equally distributed by gender. CV risk factors were common in the study population, with 33 patients (61.11%) with hypertension, 14 (25.93%) with hyperglycaemia, 20 (37.4%) with hypertriglyceridemia, 19 (35.19%) with low HDL and 64.81% with overweight. High levels of PCR were found in 24 subjects (44.44%). Right c-IMT was increased in 26.41% of the sample, and 11.32% had an atheromatous plaque. Left c-IMT was increased in 24.53% of patients, with a plaque in 7.55% of them. Clinically relevant depressive symptoms were found in the 18.87% of the sample and were statistically significantly associated with PCR (OR = 28.63; P = 0.01). Conclusions Evidence contributing to the so-called “inflammation theory” of depression and supporting the association between mood and CV disorders was here collected, supporting the need for a multidisciplinary approach to the diagnosis and treatment of such conditions, assuming a clinically-translated PNEI (psycho-neuro-endocrino-immunological) perspective

Not only seeds: a cultural ecosystem service provided by the Apennine brown bear

The unequal distribution of the costs and benefits of living with wildlife is one of the causes of human-carnivore conflicts. The existence of large carnivores is valued globally, but the costs of damages and management impacts human residents. The Apennine brown bear is endemic of central Italy and, besides its ecological value, it can attract tourists in search of nature and wilderness. The Advertising Value Equivalent of the bears' appearances in the national newspaper and on television from 2015 to 2020 was used to calculate the economic value of this flagship species as a destination image. The 11 million Euro of Advertising Value Equivalent estimated largely exceeded the amount of reimbursements sustained by the Park to manage this carnivore in the same period. This evaluation of cultural value could be used to highlight the economic benefits provided by the bear and contribute to the discussions with managers and stakeholders

Personality traits in chronic daily headache patients with and without psychiatric comorbidity: an observational study in a tertiary care headache center.

Previous studies suggest that patients with Chronic Daily Headache (CDH) have higher levels of anxiety and depressive disorders than patients with episodic migraine or tension-type headache. However, no study has considered the presence of psychiatric comorbidity in the analysis of personality traits. The aim of this study is to investigate the prevalence of psychiatric comorbidity and specific personality traits in CDH patients, exploring if specific personality traits are associated to headache itself or to the psychiatric comorbidity associated with headache.An observational, cross-sectional study. Ninety-four CDH patients with and without medication overuse were included in the study and assessed by clinical psychiatric interview and Mini International Neuropsychiatric Interview (M.I.N.I.) as diagnostic tools. Minnesota Multiphasic Personality Inventory-2 (MMPI-2), Hamilton Depression Rating Scale (HAM-D) were afterwards administered. Patients with and without psychiatric comorbidity were compared. Further analyses were made by splitting the whole group according to the headache diagnosis and the presence or not of medication overuse.Psychiatric comorbidity was detected in 44 patients (46.8\%) (group A) and was absent in the remaining 50 patients (53.2\%) (group B). Mood and anxiety disorders were the most frequently diagnosed (43.6\%).In the overall group, mean scores of MMPI-2 showed a high level in the so-called neurotic triad; in particular the mean score in the Hypochondriasis subscale was in the pathologic area (73.55 ± 13.59), while Depression and Hysteria scores were moderate but not severe (62.53 and 61.61, respectively). In content scales, score in Health Concern was also high (66.73).Group A presented higher scores compared to Group B in the following MMPI-2 subscales: Hypochondriasis (p= .036), Depression (p= .032), Hysteria (p< .0001), Hypomania (p= .030). Group B had a high score only in the Hypochondriasis subscale. No significant differences were found between chronic migraine (CM)-probable CM (pCM) plus probable medication overuse headache (pMOH) and chronic tension-type headache (CTTH)-probable CTTH (pCTTH) plus pMOH patients or between patients with and without drug overuse.The so-called "Neurotic Profile" reached clinical level only in CDH patients with psychiatric comorbidity while a high concern about their general health status was a common feature in all CDH patients

MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells.

MicroRNAs (miRNA) have rapidly emerged as modulators of gene expression in cancer in which they may have great diagnostic and therapeutic import. MicroRNA-199a-3p (miR-199a-3p) is downregulated in several human malignancies including hepatocellular carcinoma (HCC). Here, we show that miR-199a-3p targets mammalian target of rapamycin (mTOR) and c-Met in HCC cells. Restoring attenuated levels of miR-199a-3p in HCC cells led to G(1)-phase cell cycle arrest, reduced invasive capability, enhanced susceptibility to hypoxia, and increased sensitivity to doxorubicin-induced apoptosis. These in vitro findings were confirmed by an analysis of human HCC tissues, which revealed an inverse correlation linking miR-199a-3p and mTOR as well as a shorter time to recurrence after HCC resection in patients with lower miR-199a-3p expression. These results suggest that tactics to regulate mTOR and c-Met by elevating levels of miR-199a-3p may have therapeutic benefits in highly lethal cancers such as HC

MiR-122 targets serpinB3 and is involved in sorafenib resistance in hepatocellular carcinoma

The only first-line treatment approved for advanced hepatocellular carcinoma (HCC) is sorafenib. Since many patients experience drug resistance, the discovery of more effective therapeutic strategies represents an unmet clinical need. MicroRNA (MiR)-122 is downregulated in most HCCs, while oncogenic SerpinB3 is upregulated. Here, we assessed the relationship between miR-122 and SerpinB3 and their influence on cell phenotype and sorafenib resistance in HCC. A bioinformatics analysis identified SerpinB3 among hypothetical miR-122 targets. In SerpinB3-overexpressing HepG2 cells, miR-122 transfection decreased SerpinB3 mRNA and protein levels, whereas miR-122 inhibition increased SerpinB3 expression. Luciferase assay demonstrated the interaction between miR-122 and SerpinB3 mRNA. In an HCC rat model, high miR-122 levels were associated with negative SerpinB3 expression, while low miR-122 levels correlated with SerpinB3 positivity. A negative correlation between miR-122 and SerpinB3 or stem cell markers was found in HCC patients. Anti-miR-122 transfection increased cell viability in sorafenib-treated Huh-7 cells, while miR-122 overexpression increased sorafenib sensitivity in treated cells, but not in those overexpressing SerpinB3. In conclusion, we demonstrated that miR-122 targets SerpinB3, and its low levels are associated with SerpinB3 positivity and a stem-like phenotype in HCC. MiR-122 replacement therapy in combination with sorafenib deserves attention as a possible therapeutic strategy in SerpinB3-negative HCCs

Quantitative analysis of MRI-guided radiotherapy treatment process time for tumor real-time gating efficiency

Purpose: Magnetic Resonance-guided radiotherapy (MRgRT) systems allow continuous monitoring of therapy volumes during treatment delivery and personalized respiratory gating approaches. Treatment length may therefore be significantly affected by patient’s compliance and breathing control. We quantitatively analyzed treatment process time efficiency (TE) using data obtained from real-world patient treatment logs to optimize MRgRT delivery settings. Methods: Data corresponding to the first 100 patients treated with a low T hybrid MRI-Linac system, both in free breathing (FB) and in breath hold inspiration (BHI) were collected. TE has been computed as the percentage difference of the actual single fraction’s total treatment time and the predicted treatment process time, as computed by the TPS during plan optimization. Differences between the scheduled and actual treatment room occupancy time were also evaluated. Finally, possible correlations with planning, delivery and clinical parameters with TE were also investigated. Results: Nine hundred and nineteen treatment fractions were evaluated. TE difference between BHI and FB patients’ groups was statistically significant and the mean TE were 42.4%, and −0.5% respectively. No correlation was found with TE for BHI and FB groups. Planning, delivering and clinical parameters classified BHI and FB groups, but no correlation with TE was found. Conclusion: The use of BHI gating technique can increase the treatment process time significantly. BHI technique could be not always an adequate delivery technique to optimize the treatment process time. Further gating techniques should be considered to improve the use of MRgRT

Case Report: First in Human Online Adaptive MR Guided SBRT of Peritoneal Carcinomatosis Nodules: A New Therapeutic Approach for the Oligo-Metastatic Patient

Peritoneal carcinosis (PC) is characterized by poor prognosis. PC is currently treated as a locoregional disease and the possibility to perform very precise treatments such as stereotactic body radiation therapy (SBRT) has opened up new therapeutic perspectives. More recently, the introduction of Magnetic Resonance-guided Radiation Therapy (MRgRT) allowed online adaptation (OA) of treatment plan to optimize daily dose distribution based on patient’s anatomy. The aim of this study is the evaluation of the effectiveness of SBRT OA workflow in an oligometastatic patient affected by PC. We report the clinical case of a patient affected by PC originating from colon cancer, previously treated with chemotherapy and surgery, addressed to OA SBRT treatment on a single chemoresistant PC nodule, delivered with a 0.35 T MR Linac. Treatment was delivered using gating approach in deep inspiration breath hold condition in order to reduce intrafraction variability. Prescription dose was 35 Gy in 5 fractions. The PTV V95% of the original plan was 96.6%, while the predicted values for the following fractions were 11.9, 56.4, 0, 0, and 61%. Similarly, the small bowel V19.5 Gy of the original plan was 4.63 cc, while the predicted values for the following fractions were 3.7, 8.6, 10.7, 1.96, 3.7 cc. Thanks to the OA approach, the re-optimized PTV V95% coverage improved to 96.1, 89.0, 85.5, 94.5, and 94%; while the small bowel V19.5 Gy to 3.36; 3.28; 1.84; 2.62; 2.6 cc respectively. After the end of RT, the patient was addressed to follow-up, and the re-evaluation 18F-FDG PET-CT was performed after 10 months from irradiation showed complete response. No acute or late toxicities were recorded. MRgRT with OA approach in PC patients is technically and clinically feasible with clean toxicity result. Online adaptive SBRT for oligometastases opens up new therapeutic scenarios in the management of this category of patients

MiR-30e-3p influences tumor phenotype through MDM2/TP53 axis and predicts sorafenib resistance in hepatocellular carcinoma

The molecular background of hepatocellular carcinoma (HCC) is highly heterogeneous, and biomarkers predicting response to treatments are an unmet clinical need. We investigated miR-30e-3p contribution to HCC phenotype and response to sorafenib, as well as the mutual modulation of TP53/MDM2 pathway, in HCC tissues and preclinical models.MiR-30e-3p was downregulated in human and rat HCCs, and its downregulation associated with TP53 mutations. TP53 contributed to miR-30e-3p biogenesis, and MDM2 was identified among its target genes, establishing an miR-30e-3p/TP53/MDM2 feedforward loop and accounting for miR-30e-3p dual role based on TP53 status. EpCAM, PTEN, and p27 were demonstrated as miR-30e-3p additional targets mediating its contribution to stemness and malignant features. In a preliminary cohort of patients with HCC treated with sorafenib, increased miR-30e-3p circulating levels predicted the development of resistance. In conclusion, molecular background dictates miR-30e-3p dual behavior in HCC. Mdm2 targeting plays a predominant tumor suppressor function in wild-type TP53 contexts, whereas other targets such as PTEN, p27, and EpCAM gain relevance and mediate miR-30e-3p oncogenic role in nonfunctional TP53 backgrounds. Increased circulating levels of miR-30e-3p predict the development of sorafenib resistance in a preliminary series of patients with HCC and deserve future investigations. Significance: The dual role ofmiR-30e-3p inHCCclarifies how the molecular context dictates the tumor suppressor or oncogenic function played by miRNAs

Ataluren improves myelopoiesis and neutrophil chemotaxis by restoring ribosome biogenesis and reducing p53 levels in Shwachman–Diamond syndrome cells

Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA&gt;CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation