PacDOCK: A Web Server for Positional Distance-Based and Interaction-Based Analysis of Docking Results

Molecular docking is a key method for structure-based drug design used to predict the conformations assumed by small drug-like ligands when bound to their target. However, the evaluation of molecular docking studies can be hampered by the lack of a free and easy to use platform for the complete analysis of results obtained by the principal docking programs. To this aim, we developed PacDOCK, a freely available and user-friendly web server that comprises a collection of tools for positional distance-based and interaction-based analysis of docking results, which can be provided in several file formats. PacDOCK allows a complete analysis of molecular docking results through root mean square deviation (RMSD) calculation, molecular visualization, and cluster analysis of docked poses. The RMSD calculation compares docked structures with a reference structure, also when atoms are randomly labelled, and their conformational and positional differences can be visualised. In addition, it is possible to visualise a ligand into the target binding pocket and investigate the key receptor-ligand interactions. Moreover, PacDOCK enables the clustering of docking results by identifying a restrained number of clusters from many docked poses. We believe that PacDOCK will contribute to facilitating the analysis of docking results to improve the efficiency of computer-aided drug design

Efectos de la práctica del ballet clásico (psicoballet) sobre el déficit de atención de una niña de ocho años de edad

El Psicoballet es una rama de la Danza Terapia donde se utiliza el Ballet Clásico como método de intervención psicológica. Esta investigación trabajó en un estudio de caso único con una niña de 8 años de edad diagnosticada con Trastorno por Déficit de Atención (TDA),con quien se realizó una intervención por medio del Psicoballet. Se utilizó un diseño pretest postest aplicando pruebas neuropsicológicas tanto a la niña como a la mamá, antes y después de la intervención. Se miraron los cambios en las conductas propias del TDA, donde se identificó una mejoría general en el post-test, cambio después de la intervención del Ballet Clásico.Psychoballet is one of the branches belonging to dance therapy, where classical ballet is used as a psychological intervention method. This research worked in a one-study case with an 8 year old girl diagnosed with Attention Deficit Disorder (ADD), applying intensive interventions through the use of Psychoballet. The investigation carried out a pre-test -- post-test research design by applying neurophsycological tests to the girl and her mother, before and after the entire intervention. The changes in behaviours related to ADD were observed, and it was identifiable a general improvement in the post-test, change that was accomplished after the intervention of classical ballet.Psicólogo (a)Pregrad

B-TURP versus HoLEP. Peri-operative outcomes and complications in frail elderly (>75 y.o.) patients. A prospective randomized study

Background: The aim of this study was to compare the peri-operative and functional results between trans-urethral resection of the prostate (TURP) and holmium laser enucleation of the prostate (HoLEP) in the treatment of benign prostatic hyperplasia (BPH) associated with lower urinary tract symptoms (LUTS) in middle-old patients. Materials and methods: This prospective single-center study included patients over 75 years old treated with B-TURP or HoLEP for BPH associated with LUTS with prostate volume (PV) <100 mL. Primary endpoints were the intra-operative blood loss, percentage of loss of hemoglobin, blood transfusion, complications, and the comparison of functional outcomes. All patients were evaluated at 1, 3, 6, and 12 months of follow-up. Results: Overall, 96 patients undergoing HoLEP and 104 B-TURP were eligible and enrolled for the study. Post-operative results showed statistically significant differences between the two groups, all in favor of HoLEP group, specifically in terms of removed prostate tissue, PV reduction rate, hemoglobin values at 24 h, hemoglobin loss, operative time, length of hospitalization, days of catheterization, and urinary flow rates. There was no significant difference in terms of postvoid residual urine volume, perioperative complication, blood transfusion, International Prostate Symptom Score (IPSS), and IPSS quality of life scores. Conclusions: In middle-old patients, the HoLEP technique represents a prostate size-independent treatment option with a more favorable safety profile defined by less bleeding, lower blood transfusions, and a significantly lower hemoglobin drop than B-TURP

Effectiveness of clinical scores in predicting coronary artery disease in familial hypercholesterolemia: a coronary computed tomography angiography study

PurposeOne of the major challenges in the management of familial hypercholesterolemia (FH) is the stratification of cardiovascular risk in asymptomatic subjects. Our purpose is to investigate the performance of clinical scoring systems, Montreal-FH-score (MFHS), SAFEHEART risk (SAFEHEART-RE) and FH risk score (FHRS) equations and Dutch Lipid Clinic Network (DLCN) diagnostic score, in predicting extent and severity of CAD at coronary computed tomography angiography (CCTA) in asymptomatic FH.Material and methodsOne-hundred and thirty-nine asymptomatic FH subjects were prospectively enrolled to perform CCTA. MFHS, FHRS, SAFEHEART-RE and DLCN were assessed for each patient. Atherosclerotic burden scores at CCTA (Agatston score [AS], segment stenosis score [SSS]) and CAD-RADS score were calculated and compared to clinical indices.ResultsNon-obstructive CAD was found in 109 patients, while 30 patients had a CAD-RADS >= 3. Classifying the two groups according to AS, values varied significantly for MFHS (p < 0.001), FHRS (p < 0.001) and SAFEHEART-RE (p = 0.047), while according to SSS only MFHS and FHRS showed significant differences (p < 0.001). MFHS, FHRS and SAFEHEART-RE, but not DLCN, showed significant differences between the two CAD-RADS groups (p < .001).MFHS proved to have the best discriminatory power (AUC = 0.819; 0.703-0.937, p < 0.001) at ROC analysis, followed by FHRS (AUC = 0.795; 0.715-0.875, p < .0001) and SAFEHEART-RE (AUC = .725; .61-.843, p < .001).ConclusionsGreater values of MFHS, FHRS and SAFEHEART-RE are associated to higher risk of obstructive CAD and might help to select asymptomatic patients that should be referred to CCTA for secondary prevention

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours

Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro-senescence therapy for cancer

Successful treatment with pollen extract of hematospermia in patients with xanthogranolomatous prostatitis

Introduction: The aim of this study was to report our experience in the management of hematospermia observed in 16 patients suffering from xanthogranulomatous prostatitis. Methods: Recurrent episodes of hematospermia were the onset symptom in all patients, and in 25% of patients it was combined with fever. All patients reported PSA value elevation and the digital rectal examination (DRE) revealed an increase of the gland size and of its consistency in all cases. In all patients, the hematospermia was treated with the oral administration of two tablets of pollen extract in a single (1 g) dose daily for 30 days. Results: Sixteen patients were observed between 2008 and 2016, referring hematospermia, progressive lower urinary tract symptoms (LUTS), and serum PSA level increase. To exclude the prostate cancer presence all patients were submitted to transperineal TRUS guided biopsy. In all the patients complete resolution of hematospermia was achieved treatment with pollen extract. All patients were subsequently treated for LUTS (alpha-adrenergic blockers), but none reported any significant improvement of symptoms. Basing on these pieces of evidence, after 90 days of alpha-blockers therapy, all patients underwent bipolar TURP. Histological examination of resected prostatic tissue revealed in all patients the diagnosis of xanthogranulomatous prostatitis. Conclusions: Patients with xanthogranulomatous prostatitis especially experience irritative symptoms, sometimes combined with fever or hematospermia. Hematospermia as the onset symptom has not been reported so far. The administration of the pollen extract for 30 days was associated with a complete resolution of hematospermia

Insight into immune profile associated with vitiligo onset and anti-tumoral response in melanoma patients receiving anti-PD-1 immunotherapy

IntroductionImmunotherapy with checkpoint inhibitors is an efficient treatment for metastatic melanoma. Development of vitiligo upon immunotherapy represents a specific immune-related adverse event (irAE) diagnosed in 15% of patients and associated with a positive clinical response. Therefore, a detailed characterization of immune cells during vitiligo onset in melanoma patients would give insight into the immune mechanisms mediating both the irAE and the anti-tumor response. MethodsTo better understand these aspects, we analyzed T cell subsets from peripheral blood of metastatic melanoma patients undergoing treatment with anti-programmed cell death protein (PD)-1 antibodies. To deeply characterize the antitumoral T cell response concomitant to vitiligo onset, we analyzed T cell content in skin biopsies collected from melanoma patients who developed vitiligo. Moreover, to further characterize T cells in vitiligo skin lesion of melanoma patients, we sequenced T cell receptor (TCR) of cells derived from biopsies of vitiligo and primary melanoma of the same patient.Results and discussionStratification of patients for developing or not developing vitiligo during anti-PD-1 therapy revealed an association between blood reduction of CD8-mucosal associated invariant T (MAIT), T helper (h) 17, natural killer (NK) CD56bright, and T regulatory (T-reg) cells and vitiligo onset. Consistently with the observed blood reduction of Th17 cells in melanoma patients developing vitiligo during immunotherapy, we found high amount of IL-17A expressing cells in the vitiligo skin biopsy, suggesting a possible migration of Th17 cells from the blood into the autoimmune lesion. Interestingly, except for a few cases, we found different TCR sequences between vitiligo and primary melanoma lesions. In contrast, shared TCR sequences were identified between vitiligo and metastatic tissues of the same patient. These data indicate that T cell response against normal melanocytes, which is involved in vitiligo onset, is not typically mediated by reactivation of specific T cell clones infiltrating primary melanoma but may be elicited by T cell clones targeting metastatic tissues. Altogether, our data indicate that anti-PD-1 therapy induces a de novo immune response, stimulated by the presence of metastatic cells, and composed of different T cell subtypes, which may trigger the development of vitiligo and the response against metastatic tumor

ETS-related gene (ERG) undermines genome stability in mouse prostate progenitors via Gsk3β dependent Nkx3.1 degradation.

21q22.2-3 deletion is the most common copy number alteration in prostate cancer (PCa). The genomic rearrangement results in the androgen-dependent de novo expression of ETS-related gene (ERG) in prostate cancer cells, a condition promoting tumor progression to advanced stages of the disease. Interestingly, ERG expression characterizes 5-30% of tumor precursor lesions - High Grade Prostatic Intraepithelial Neoplasia (HGPIN) - where its role remains unclear. Here, by combining organoids technology with Click-chemistry coupled Mass Spectrometry, we demonstrate a prominent role of ERG in remodeling the protein secretome of prostate progenitors. Functionally, by lowering autocrine Wnt-4 signaling, ERG represses canonical Wnt pathway in prostate progenitors, and, in turn, promotes the accumulation of DNA double strand breaks via Gsk3β-dependent degradation of the tumor suppressor Nkx3.1. On the other hand, by shaping extracellular paracrine signals, ERG strengthens the pro-oxidative transcriptional signature of inflammatory macrophages, which we demonstrate to infiltrate pre-malignant ERG positive prostate lesions. These findings highlight previously unrecognized functions of ERG in undermining adult prostate progenitor niche through cell autonomous and non-autonomous mechanisms. Overall, by supporting the survival and proliferation of prostate progenitors in the absence of growth stimuli and promoting the accumulation of DNA damage through destabilization of Nkx3.1, ERG could orchestrate the prelude to neoplastic transformation

Induction of immunosuppressive functions and NF-\u3baB by FLIP in monocytes

Immunosuppression is a hallmark of tumor progression, and treatments that inhibit or deplete monocytic myeloid-derived suppressive cells could promote anti-tumor immunity. c-FLIP is a central regulator of caspase-8-mediated apoptosis and necroptosis. Here we show that low-dose cytotoxic chemotherapy agents cause apoptosis linked to c-FLIP down-regulation selectively in monocytes. Enforced expression of c-FLIP or viral FLIP rescues monocytes from cytotoxicity and concurrently induces potent immunosuppressive activity, in T cell cultures and in vivo models of tumor progression and immunotherapy. FLIP-transduced human blood monocytes can suppress graft versus host disease. Neither expression of FLIP in granulocytes nor expression of other anti-apoptotic genes in monocytes conferred immunosuppression, suggesting that FLIP effects on immunosuppression are specific to monocytic lineage and distinct from death inhibition. Mechanistically, FLIP controls a broad transcriptional program, partially by NF-\u3baB activation. Therefore, modulation of FLIP in monocytes offers a means to elicit or block immunosuppressive myeloid cells