Computational Methods in Biophysics and Medicinal Chemistry: Applications and Challenges

In this thesis I described the theory and application of several computational methods in solving medicinal chemistry and biophysical tasks. I pointed out to the valuable information which could be achieved by means of computer simulations and to the possibility to predict the outcome of traditional experiments. Nowadays, computer represents an invaluable tool for chemists. In particular, the main topics of my research consisted in the development of an automated docking protocol for the voltage-gated hERG potassium channel blockers, and the investigation of the catalytic mechanism of the human peptidyl-prolyl cis-trans isomerase Pin1

L’utilizzo delle protesi endoscopiche nella patologia dell’apparato digerente

L’utilizzo di protesi ad introduzione per via endoscopica per patologie dell’apparato digerente sia benigne che maligne ha avuto negli ultimi anni un considerevole sviluppo. Il posizionamento delle endoprotesi è ben tollerato dai pazienti, non necessita di anestesia e comporta rischi relativamente minimi. Le nuove protesi metalliche autoespansibili permettono di risolvere stenosi anche molto serrate senza quasi mai necessità di dilatazione, con riduzione dei rischi che da questa derivano. Viene riportata una revisione dell’esperienza di protesizzazione per patologie dell’apparato digerente e vengono discussi le indicazioni, i limiti e le complicanze, sulla scorta dei dati dalla letteratura internazionale

Inner peripheries : dealing with peripherality and marginality issues within the European policy framework

Inner Peripheries is a complex and often misinterpreted concept, as demonstrated by current scientific evidence. Such complexity derives from the intrinsic peripherality and marginality characteristics of the Inner Peripheries. Despite Inner Peripheries suffer from geographical and socio-economic disparities, their environmental, social and economic potentialities are not fully expressed, and thus can be further strengthened by both the EU Cohesion and Rural Development Policies. However, there is currently a lack of knowledge about the linkages between the Inner Peripheries and both Cohesion and Rural Development Policies, which could limit the effectiveness of planning strategies in these territories. Therefore, through a structured review, we explore the linkages between Inner Peripheries and peripherality and marginality concepts and related criticalities and opportunities. Moreover, we consider the relationships between Inner Peripheries and Cohesion Policy Thematic Objectives and Rural Development Policy Priorities. The main findings show that the Inner Peripheries concept needs to be further explored, especially concerning the environmental aspects. Accordingly, we suggest that great challenges and opportunities currently exist in these territories, and combined policies efforts need to be oriented to strengthen the future sustainable development in the Inner Peripheries..   Key words: Review, Rural Development Policy, Cohesion Policy, Inner Areas.    Resumen: Inner Peripheries es un concepto complejo y a menudo mal interpretado, como lo demuestran las pruebas científicas actuales. Tal complejidad deriva de sus intrínsecas características de periferia y marginalidad. A pesar de que las Inner Peripheries sufren de disparidades geográficas y socioeconómicas, sus potencialidades ambientales, sociales y económicas no se expresan completamente y, por lo tanto, pueden ser reforzadas por las Políticas de Cohesión y Desarrollo Rural de la UE. Sin embargo, actualmente existe una falta de conocimiento sobre los vínculos entre las Periferia Interior y las Políticas de Cohesión y Desarrollo Rural, lo que podría limitar la efectividad de las estrategias de planificación en estos territorios. A través de una revisión estructurada, exploramos los vínculos entre las Inner Peripheries y los conceptos de periferia y marginalidad y las críticas y oportunidades relacionadas. Además, consideramos las relaciones entre las Inner Peripheries y los objetivos temáticos de la Política de Cohesión y las Prioridades de la Política de Desarrollo Rural. Los principales hallazgos muestran que el concepto de Inner Peripheries necesita ser explorado más a fondo, especialmente en relación con los aspectos ambientales. Sugerimos que actualmente existen grandes desafíos y oportunidades en estos territorios, y que los esfuerzos de políticas combinadas deben orientarse para fortalecer el desarrollo sostenible futuro en las Inner Peripheries.   Palabras clave: Revisión; Política De Desarrollo Rural; Política De Cohesión; Áreas Internas

A patient-centered multidisciplinary cardiac rehabilitation program improves glycemic control and functional outcome in coronary artery disease after percutaneous and surgical revascularization

Background: Cardiac rehabilitation (CR) is strongly associated with all-cause mortality reduction in patients with coronary artery disease (CAD). The impact of CR on pathological risk factors, such as impaired glucose tolerance (IGT), and functional recovery remains under debate. The aim of the present study is to determine whether CR has a positive effect on physical exercise improvement and on pathological risk factors in IGT and diabetic patients with CAD. Methods: One hundred and seventy-one consecutive patients participating in a 3-month CR from January 2014 to June 2015 were enrolled. The primary endpoint was defined as an improvement of peak workload and VO2-peak; glycated hemoglobin (HbA1c) reduction was considered as a secondary endpoint. Results: Euglycemic patients presented a significant improvement in peak workload compared to diabetic patients (from 5.75 ± 1.45 to 6.65 ± 1.84 METs, p = 0.018 vs. 4.8 ± 0.8 to 4.9 ± 1.4 METs). VO2-peak improved in euglycemic patients (VO2-peak from 19.3 ± 5.3 mL/min/kg to 22.5 ± 5.9, p = 0.003), while diabetic patients did not present  a  statistically significant trend (VO2-peak from 16.9 ± 4.4 mL/min/kg to 18.0 ± 3.8, p < 0.056). Diabetic patients have benefited more in terms of blood glucose control compared to IGT patients (HbA1c from 7.7 ± 1.0 to 7.4 ± 1.1 compared to 5.6 ± 0.4 to 5.9 ± 0.5, p = 0.02, respectively). Conclusions: A multidisciplinary CR program improves physical functional capacity in CAD setting, particularly in euglycemic patients. IGT patients as well as diabetic patients may benefit from a CR program, but long-term outcome needs to be clarified in larger studies

Argonaute 2 drives miR-145-5p-dependent gene expression program in breast cancer cells

To perform their regulatory functions, microRNAs (miRNAs) must assemble with any of the four mammalian Argonaute (Ago) family of proteins, Ago1–4, into an effector complex known as the RNA-induced silencing complex (RISC). While the mature miRNA guides the RISC complex to its target mRNA, the Ago protein represses mRNA translation. The specific roles of the various Ago members in mediating miRNAs activity, however, haven’t been clearly established. In this study, we investigated the contribution of Ago2, the only human Ago protein endowed with nuclease activity, to the function of tumor-suppressor miR-145-5p in breast cancer (BC). We show that miR-145-5p and Ago2 protein are concomitantly downregulated in BC tissues and that restoration of miR-145-5p expression in BC cells leads to Ago2 protein induction through the loosening of Ago2 mRNA translational repression. Functionally, miR-145-5p exerts its inhibitory activity on cell migration only in presence of Ago2, while, upon Ago2 depletion, we observed increased miR-145/Ago1 complex and enhanced cell motility. Profiling by microarray of miR-145-5p target mRNAs, in BC cells depleted or not of Ago2, revealed that miR-145-5p drives Ago2-dependent and -independent activities. Our results highlight that the Ago2 protein in cancer cells strictly dictates miR-145-5p tumor suppressor activity

Local lymph node involvement in pediatric renal cell carcinoma: A report from the Italian TREP project

Background. One of the most important adverse prognostic factors for adult renal cell carcinoma (RCC) is the retroperitoneal lymph node involvement. The aim of this article is to study the prognostic significance of local lymph node involvement in pediatric RCC and the role of retroperitoneal lymph node dissection (RLND) at diagnosis. Procedure. The series included 16 patients with RCC and lymph nodes involvement registered in the Italian Rare Tumors Pediatric Age (TREP) project, accounting for 26.2% of 61 pediatric RCC observed at AIEOP centers. Results. A radical nephrectomy was performed in all cases: at diagnosis in 12 cases, after preoperative chemotherapy (CT) in 4 cases. As a part of the same procedure 9 patients underwent RLND, and 7 received a more limited lymph nodes resection. Five (31.2%) developed disease recurrence 2-34 months after diagnosis (median, 6 months) plus 1 developed progression; 6 patients died, 1 of them from secondary leukemia. Among the nine patients receiving RLND, eight are alive and disease free. This compares with only one patient surviving among the seven receiving a more limited lymph nodes resection. The estimated 25-year PFS and OS rates for all patients were 61.4% (95% CI 33.2-80.5) and 50.8% (95% CI 16.5-77.5), respectively. Conclusions. Lymph node involvement is an unfavorable prognostic factor in children with RCC. RLND appears to be a critical factor to improve the outcome. However, when compared to similar adult patients, the outcome in children appears to be better, suggesting that pediatric RCC, or the host, may be critical differences. © 2008 Wiley-Liss, Inc

Evidence for preferences of Italian patients for physician attire

BACKGROUND: The relationship between patient and physician is a complex interaction that includes multiple factors. The objective of this study was to explore Italian patients' preferences regarding physician appearance. METHODS: A questionnaire was developed to survey patients in different medical and surgical settings; each subject was asked to choose one picture of either a male or female physician from a selection of different attires (professional, casual, surgical scrubs, trendy, and careless). Patients were also surveyed about issues such as the presence of a name tag, hair length, trousers on women, amount of makeup, presence of tattoos, and body piercing. Statistical analysis was performed using a Chi-square test. RESULTS: A total of 765 questionnaires (534 completed from patients waiting for an internal medicine visit and 231 for other subspecialties) were completed. The majority (45%) of patients preferred the gastroenterologist to wear a surgical scrub with a white coat. For the other specialists, patients accepted either scrubs or formal dress under a white coat (P ≤ 0.05), with a name tag. Trendy attire was preferred by nine patients (1.1%). The entire sample judged it inappropriate for clinicians to have long hair, visible tattoos, body piercing, and, for women, to wear trousers and use excessive makeup. CONCLUSION: This is the first study conducted in Italy regarding physician attire. As in other Western countries, Italian patients favor physicians in professional attire with a white coat. Wearing professional dress is part of "etiquette based medicine" and may favorably influence clinician-patient relationships and patient compliance.</br

Adjuvant High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Support for High-Risk Primary Breast Cancer: Results from the Italian National Registry

n/

The mechanics of congenital heart disease: from a morphological trait to the functional echocardiographic evaluation

Advances in pediatric cardiac surgery have resulted in a recent growing epidemic of children and young adults with congenital heart diseases (CHDs). In these patients, congenital defects themselves, surgical operations and remaining lesions may alter cardiac anatomy and impact the mechanical performance of both ventricles. Cardiac function significantly influences outcomes in CHDs, necessitating regular patient follow-up to detect clinical changes and relevant risk factors. Echocardiography remains the primary imaging method for CHDs, but clinicians must understand patients' unique anatomies as different CHDs exhibit distinct anatomical characteristics affecting cardiac mechanics. Additionally, the use of myocardial deformation imaging and 3D echocardiography has gained popularity for enhanced assessment of cardiac function and anatomy. This paper discusses the role of echocardiography in evaluating cardiac mechanics in most significant CHDs, particularly its ability to accommodate and interpret the inherent anatomical substrate in these conditions

Cyclic Vomiting Syndrome in Children

Cyclic Vomiting Syndrome (CVS) is an underdiagnosed episodic syndrome characterized by frequent hospitalizations, multiple comorbidities, and poor quality of life. It is often misdiagnosed due to the unappreciated pattern of recurrence and lack of confirmatory testing. CVS mainly occurs in pre-school or early school-age, but infants and elderly onset have been also described. The etiopathogenesis is largely unknown, but it is likely to be multifactorial. Recent evidence suggests that aberrant brain-gut pathways, mitochondrial enzymopathies, gastrointestinal motility disorders, calcium channel abnormalities, and hyperactivity of the hypothalamic-pituitary-adrenal axis in response to a triggering environmental stimulus are involved. CVS is characterized by acute, stereotyped and recurrent episodes of intense nausea and incoercible vomiting with predictable periodicity and return to baseline health between episodes. A distinction with other differential diagnoses is a challenge for clinicians. Although extensive and invasive investigations should be avoided, baseline testing toward identifying organic causes is recommended in all children with CVS. The management of CVS requires an individually tailored therapy Management of acute phase is mainly based on supportive and symptomatic care. Early intervention with abortive agents during the brief prodromal phase can be used to attempt to terminate the attack. During the interictal period, non-pharmacologic measures as lifestyle changes and the use of reassurance and anticipatory guidance seem to be effective as a preventive treatment. The indication for prophylactic pharmacotherapy depends on attack intensity and severity, the impairment of the QoL and if attack treatments are ineffective or cause side effects. When children remain refractory to acute or prophylactic treatment, or the episode differs from previous ones, the clinician should consider the possibility of an underlying disease and further mono- or combination therapy and psychotherapy can be guided by accompanying comorbidities and specific sub-phenotype. This review was developed by a joint task force of the Italian Society of Pediatric Gastroenterology Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP) to identify relevant current issues and to propose future research directions on pediatric CV