A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells

Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcription factor that acts as the master regulator of cellular response to reduced oxygen levels, thus playing a key role in the adaptation, survival and progression of tumors. Here we report cyclo-CLLFVY, identified from a library of 3.2 million cyclic hexapeptides using a genetically encoded high-throughput screening platform, as an inhibitor of the HIF-1α/HIF-1β protein-protein interaction in vitro and in cells. The identified compound inhibits HIF-1 dimerization and transcription activity by binding to the PAS-B domain of HIF-1α, reducing HIF-1-mediated hypoxia response signaling in a variety of cell lines, without affecting the function of the closely related HIF-2 isoform. The reported cyclic peptide demonstrates the utility of our high-throughput screening platform for the identification of protein-protein interaction inhibitors, and forms the starting point for the development of HIF-1 targeted cancer therapeutics

ACTA OTORHINOLARYNGOLOGICA ITALICA

Presentiamo un caso di posizionamento di impianto cocleare in un uomo di 50 anni che, dopo aver subito tre anni prima un intervento per via retrosigmoidea per un neurinoma dellacustico in stadio 1, è stato colpito da ipoacusia improvvisa ipsilaterale sviluppando un intenso acufene. Dopo lattivazione dellimpianto lacufene è sceso da un grado 4 ad un grado 2 secondo il THI. Sono migliorate le capacità di localizzazione. Lascolto nel rumore (S/R + 7 dB) con il segnale proveniente dal lato operato è migliorato da 38 a 100%. Abbiamo inoltre verificato un significativo incremento dei punteggi relativi a spazialità e linguaggio del questionario Speech, spatial and qualities of sounds. In conclusione limpianto cocleare è una soluzione praticabile ed efficace in caso di insorgenza di ipoacusia ritardata dopo chirurgia conservativa del neurinoma dellacustico

Systematic review of the literature on the clinical effectiveness of the cochlear implant procedure in adult patients

The aim of this systematic review was to summarize the results of scientific publications on the clinical effectiveness of the cochlear implant (CI) procedure in adults. The members of the Working Group first examined existing research evidence from the national and international literature and main international guidelines. They considered as universally accepted the usefulness/effectiveness of unilateral cochlear implantation in severelyprofoundly adult patients. Accordingly, they focused their attention on the systematic reviews addressing clinical effectiveness and cost/efficacy of CI procedures, with particular regard to the most controversial issues for which international consensus is still lacking. The following aspects were evaluated: monolateral CI in advanced-age adult patients; bilateral (simultaneous/sequential) CI vs. unilateral CI and vs. bimodal stimulation; benefits derived from the monolateral CI procedure in adult patients with prelingual deafness. With regard to CI in elderly patients, the selected studies document an improvement of the quality of life and perceptive abilities after CI, even if the benefits were found to be inferior in patients over 70 years at the time of surgery. Thus, from the results of the studies included in the review, advanced age is not a contraindication for the CI procedure. With respect to unilateral CI, bilateral CI offers advantages in hearing in noise, in sound localization and less during hearing in a silent environment. However, high interindividual variability is reported in terms of benefits from the second implant. With regard to CI in prelingually deaf adults, the selected studies document benefits deriving from the CI procedure in terms of improvement of perceptive abilities and in the quality of life after CI, as well as subjectively perceived benefits. However, there is high interindividual variability and the study sample is limited

p53-Mediated downregulation of H ferritin promoter transcriptional efficiency via NF-Y

The tumor suppressor protein p53 triggers many of the cellular responses to DNA damage by regulating the transcription of a series of downstream target genes. p53 acts on the promoter of the target genes by interacting with the trimeric transcription factor NF-Y. H ferritin promoter activity is tightly dependent on a multiprotein complex called Bbf; on this complex NF-Y plays a major role. The aim of this work was to study the modulation of H ferritin expression levels by p53. CAT reporter assays indicate that: (i) p53 overexpression strongly downregulates the transcriptional efficiency driven by an H ferritin promoter construct containing only the NF-Y recognition sequence and that the phenomenon is reverted by p53 siRNA; (ii) the p53 C-terminal region is sufficient to elicitate this regulation and that a correct C-terminal acetylation is also required. The H ferritin promoter displays no p53-binding sites; chromatin immunoprecipitation assays indicate that p53 is recruited on this promoter by NF-Y. The p53–NF-Y interaction does not alter the NF-Y DNA-binding ability as indicated by electrophoretic mobility shift assay (EMSA) analysis. These results demonstrate that the gene coding for the H ferritin protein belongs to the family of p53-regulated genes, therefore adding a new level of complexity to the regulation of the H ferritin transcription and delineate a role for this protein in a series of cellular events triggered by p53 activation

Aerothermodynamic Analysis of a Reentry Brazilian Satellite

This work deals with a computational investigation on the small ballistic reentry Brazilian vehicle SARA (acronyms for SAt\'elite de Reentrada Atmosf\'erica). Hypersonic flows over the vehicle SARA at zero-degree angle of attack in a chemical equilibrium and thermal non-equilibrium are modeled by the Direct Simulation Monte Carlo (DSMC) method, which has become the main technique for studying complex multidimensional rarefied flows, and that properly accounts for the non-equilibrium aspects of the flows. The emphasis of this paper is to examine the behavior of the primary properties during the high altitude portion of SARA reentry. In this way, velocity, density, pressure and temperature field are investigated for altitudes of 100, 95, 90, 85 and 80 km. In addition, comparisons based on geometry are made between axisymmetric and planar two-dimensional configurations. Some significant differences between these configurations were noted on the flowfield structure in the reentry trajectory. The analysis showed that the flow disturbances have different influence on velocity, density, pressure and temperature along the stagnation streamline ahead of the capsule nose. It was found that the stagnation region is a thermally stressed zone. It was also found that the stagnation region is a zone of strong compression, high wall pressure. Wall pressure distributions are compared with those of available experimental data and good agreement is found along the spherical nose for the altitude range investigated.Comment: The paper will be published in Vol. 42 of the Brazilian Journal of Physic

Microfluidic platforms for cell cultures and investigations

This review covers several aspects of microfluidic devices used for culturing and monitoring of both adherent and non-adherent cells, including a multitude of applications. A comparison of available platforms with high throughput analysis, automation capability, interface to sensors and integration, is reported. Aspects, such as operational versatility of the devices, are scrutinized in terms of their analytical efficacy. It is found that due to multi-functionality capability of modern microfluidics, there is big amount of experimental data obtainable from a single device, allowing complex experimental control and efficient data correlation, particularly important when biomedical studies are considered. Hence several examples on cell culture and monitoring are given in this review, including details on design of microfluidic devices with their distinctive technological peculiarities

Current trends on subtotal petrosectomy with cochlear implantation in recalcitrant chronic middle ear disorders Attualità in tema di petrosectomia subtotale con impianto cocleare nelle patologie croniche dellorecchio medio recalcitranti

Obiettivo. Stabilire la sicurezza ed efficacia dell’intervento di petrosectomia subtotale con posizionamento di impianto cocleare nei pazienti affetti da patologia cronica dell’orecchio medio refrattaria a precedenti trattamenti chirurgici. Metodi. È stato svolto uno studio retrospettivo multicentrico riguardante quei pazienti af- fetti da patologie croniche dell’orecchio medio recalcitranti, sottoposti a petrosectomia subtotale con posizionamento di impianto cocleare. Le informazioni sono state raccolte dai database di 11 centri di riferimento di III livello in Italia. A complemento, è stata svolta una revisione della più recente letteratura. Risultati. Nello studio sono stati inclusi 55 pazienti con un follow-up medio di 44 mesi. Il colesteatoma ha rappresentato la più comune pato- logia ricorrente dell’orecchio medio e il 50,9% dei pazienti aveva una cavità aperta. L’80% dei pazienti è stato sottoposto ad una chirurgia a singolo stadio. Sette pazienti hanno mostrato complicanze post-operatorie, di cui un caso di espianto. Conclusioni. L’intervento di petrosectomia subtotale con posizionamento di impianto cocleare rappresenta una tecnica chirurgica di riferimento per la gestione dei pazienti affetti da otite media cronica recalcitrante. L’intervento chirurgico a singolo stadio è la strategia più frequentemente raccomandata. Il follow-up ottimale è ancora ad oggi oggetto di dibattito. Sono richiesti ulteriori studi per stabilire il ruolo di questo intervento nei pazienti pediatrici.Objective. To establish the safety and effectiveness of subtotal petrosectomy with cochlear implantation in patients affected by chronic middle ear disorders to refractory to previous surgical treatments. Methods. A multicentre, retrospective study was conducted on patients affected by recalcitrant chronic middle ear disorders who underwent cochlear implantation in combination with subtotal petrosectomy. Patients’ details were collected from databases of 11 Italian tertiary referral centres. Additionally, a review of the most updated literature was carried out. Results. 55 patients were included with a mean follow-up time of 44 months. Cholesteatoma was the most common middle ear recurrent pathology and 50.9% of patients had an open cavity. 80% of patients underwent a single stage surgery. One case of explantation for device failure was reported among the 7 patients with post-operative complications. Conclusions. Subtotal petrosectomy with cochlear implantation is a benchmark for management of patients with recalcitrant chronic middle ear disorders. A single stage procedure is the most recommended strategy. Optimal follow-up is still debated. Further studies are required to investigate the role of this surgery in paediatric patients

A registry for the collection of data in cochlear implant patients

The need to optimize the use of all the information that modern technological tools have made available to the physician ENT/audiologist has increasingly emerged within the Italian scientific community. Towards this purpose, it is necessary to create a registry of the patients using cochlear implants (CIs). This registry will include a homogeneous summary of the information deriving from multiple sources related to daily clinical practice, in order to assess auditory benefits, safety and reliability in patients with cochlear implants, and organization over the national territory. The primary objectives relative to the above-mentioned analysis are to assess the impact of the use of cochlear implants on patient health, to ensure traceability of the devices currently used, monitoring their safety and reliability over time, to guarantee access of the technique in clinical and organizational conditions that can allow the best possible benefits. The aspects concerning implementation of the registry were discussed extensively during the first meetings of the Working Group (WG). In particular, owing to the complexity and high costs related mainly to the development of the technological aspects and the need to involve technological partners external to the WG, and to respect current privacy laws, the WG members decided that the project should be limited to proposal of a paper registry to be implemented at a later stage, possibly within the framework of successive research projects. During meetings, the WG members discussed various aspects of implementation of the registry, and in particular the scientific features connected to objectives, inclusion criteria, and structure of the forms needed for data collection and organizational aspects. A registry is proposed herein

Analysis of the impact of professional involvement in evidence generation for the HTA Process, subproject “Cochlear Implants”: methodology, results and recommendations

The aim of Health Technology Assessment (HTA) is to provide decision-makers, distributors and recipients with information on the effectiveness, cost and impact of health technologies. The present study constitutes a subproject within the wider project “Analysis of the impact of professional involvement in evidence generation for the HTA process”, which is part of the strategic programme “Transfer of the results of the research in clinical practice and organisation of healthcare services”, coordinated by Laziosanità – Agency of Public Healthcare of the Lazio Region and AgeNaS (National Agency for Regional Healthcare Services). The objectives of the present subproject (cochlear implants) are as follows: a) to produce a report regarding the health impact of cochlear implants (CI) on their recipients, through a systematic review of literature and extensive selection of relative studies, combining the outcomes with metanalytical techniques. Output: report on the indications of usage in the groups of population for which benefits are controversial; b) to create a registry of patients using cochlear implants. The registry should contain a selection of anagraphic and clinical information relative to patient follow-up in order to assess factors associated with safety and impact on cochlear implant users. This source of information is essential for future observational studies. This was divided into 4 phases: 1st phase: definition of key participants in the assessment process; 2nd phase: definition of methods and timing of “Aims” (definition of the objective); 3rd phase: definition of the methods and times of the “assessment process”, 4th phase: production of the final report. From the analysis of systematic reviews and italian and international guidelines, the Working Group members approved recommendations on the following topics: results after CI in children in relation to age at implantation, bilateral CI in children, CI in deaf children with associated disabilities, CI in adults with advanced age, bilateral CI in adults and CI in adults with pre-lingual deafness. These recommendations have also been evaluated by the Consulting Committee members and approved with minimal suggestions