Investigating the inhibition of FTSJ1 a tryptophan tRNA-specific 2’-O-methyltransferase by NV TRIDs, as a mechanism of readthrough in nonsense mutated CFTR

Abstract: Cystic Fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the CFTR gene, coding for the CFTR chloride channel. About 10% of the CFTR gene mutations are "stop" mutations, which generate a Premature Termination Codon (PTC), thus synthesizing a truncated CFTR protein. A way to bypass PTC relies on ribosome readthrough, which is the ri-bosome’s capacity to skip a PTC, thus generating a full-length protein. “TRIDs” are molecules exerting ribosome readthrough; for some, the mechanism of action is still under debate. We in-vestigate a possible mechanism of action (MOA) by which our recently synthesized TRIDs, namely NV848, NV914, and NV930, could exert their readthrough activity by in silico analysis and in vitro studies. Our results suggest a likely inhibition of FTSJ1, a tryptophan tRNA-specific 2’-O-methyltransferase

Report on first international workshop on robotic surgery in thoracic oncology

A workshop of experts from France, Germany, Italy, and the United States took place at Humanitas Research Hospital Milan, Italy, on February 10 and 11, 2016, to examine techniques for and applications of robotic surgery to thoracic oncology. The main topics of presentation and discussion were robotic surgery for lung resection; robot-assisted thymectomy; minimally invasive surgery for esophageal cancer; new developments in computer-assisted surgery and medical applications of robots; the challenge of costs; and future clinical research in robotic thoracic surgery. The following article summarizes the main contributions to the workshop. The Workshop consensus was that since video-assisted thoracoscopic surgery (VATS) is becoming the mainstream approach to resectable lung cancer in North America and Europe, robotic surgery for thoracic oncology is likely to be embraced by an increasing numbers of thoracic surgeons, since it has technical advantages over VATS, including intuitive movements, tremor filtration, more degrees of manipulative freedom, motion scaling, and high-definition stereoscopic vision. These advantages may make robotic surgery more accessible than VATS to trainees and experienced surgeons and also lead to expanded indications. However, the high costs of robotic surgery and absence of tactile feedback remain obstacles to widespread dissemination. A prospective multicentric randomized trial (NCT02804893) to compare robotic and VATS approaches to stages I and II lung cancer will start shortly

Valutazione dell'azione readthorough della molecola PTC124 su sistemi modello cellulari contenenti mutazioni non senso e in cellule epiteliali bronchiali IB3.1 (delF508/W1282X) derivate da pazienti affetti da fibrosi cistica.

Circa il 10% dei pazienti affetti da fibrosi cistica (FC) presenta nel gene CFTR mutazioni non senso (o 'stop': UGA, UAG or UAA, mutazioni di classe I) che bloccano prematuramente la sintesi della proteina. Attualmente non esiste una cura per questo tipo di mutazioni ma si sta cercando di individuare delle molecole che siano in grado di indurre la traduzione di codoni di stop prematuri (readthrough) che, rispetto a molecole già note come il G418, abbiano effetti collaterali ridotti ed una maggiore specificità per uno specifico codone. Una piccola molecola che sembra possedere una tale attività è il PTC124 (Welch, 2007). Ad oggi però non c’è ancora un consenso generale sul meccanismo di azione di questa molecola (stabilizzazione proteica, superamento del codone stop o altri meccanismi) (Welch, 2007; Auld, 2009). Al fine di chiarirlo abbiamo introdotto nel gene codificante la proteina GFP del plasmide pBOS-H2BGFP un codone di stop TGA mediante mutagenesi sito diretta. Cellule HeLa trasfettate con questo vettore e cellule IB3.1 (FC) sono state utilizzate per valutare la capacità di indurre readthrough del PTC124

Robotic Lobectomy for the Treatment of Early Stage Lung Cancer

Objective: We analysed the feasibility and safety of robotic approach for the treatment of early stage lung cancer with standard lobectomy and describe the technique of robotic assisted lobectomy (RAL)and mediastinal lymph node dissection (MLD). Methods: During a 21 months period (Dec 2006-Sept 2008), 54 patients underwent RAL for early stage lung cancer at our Institute. The approach included three ports and one utility incision. Dissection and isolation of the hilar structures was performed using the four arms Da Vinci System. Vascular and bronchial resections were done with the use of standard endoscopic staplers. Standard MLD was performed after completion of the lobectomy. The 54 patients were individually matched for age (\ub1 5 years), sex, stage, nodal status and forced expiratory ventilation in 1 sec with patients who underwent open lobectomy in the same institute during the same period and were divided into three series based on the learning curve according to duration of surgery. Results: In 7 patients (13%) conversion from RAL to open surgery was necessary because of absence of fissure in 5, oncological reason and anatomical reason of the chest in each one. The number of overall postoperative complications (20%, p=0.88) and the mean number of lymph nodes removed (18.1 \ub1 7.9 in open versus 16.8 \ub1 7.5 in RAL, p=0.43) were similar in both groups. The median time for RAL decreased by 52 minutes between the first and the last two series of interventions (p=0.01). The median length of post-operative stay was significantly shorter after RAL than after open interventions (4.5 days robotic in the third series vs. 6 days open, p=0.006). Conclusion: RAL with MLD is a feasible and safe procedure. It is an acceptable treatment for early stage lung cancer with equal results to open surgery during the early postoperative course. The benefit in terms of postoperative pain, respiratory function and quality of life are under evaluation in a prospective case control study and oncological long term results will be evaluated

Design and preliminary validation of a high-fidelity vascular simulator for robot-assisted manipulation

Abstract The number of robot-assisted minimally invasive surgeries is increasing annually, together with the need for dedicated and effective training. Surgeons need to learn how to address the novel control modalities of surgical instruments and the loss of haptic feedback, which is a common feature of most surgical robots. High-fidelity physical simulation has proved to be a valid training tool, and it might help in fulfilling these learning needs. In this regard, a high-fidelity sensorized simulator of vascular structures was designed, fabricated and preliminarily validated. The main objective of the simulator is to train novices in robotic surgery to correctly perform vascular resection procedures without applying excessive strain to tissues. The vessel simulator was integrated with soft strain sensors to quantify and objectively assess manipulation skills and to provide real-time feedback to the trainee during a training session. Additionally, a portable and user-friendly training task board was produced to replicate anatomical constraints. The simulator was characterized in terms of its mechanical properties, demonstrating its realism with respect to human tissues. Its face, content and construct validity, together with its usability, were assessed by implementing a training scenario with 13 clinicians, and the results were generally positive

Impact of Heavy Metals in Eggs and Tissues of C. caretta along the Sicilian Coast (Mediterranean Sea)

In this study we compared the heavy metal concentration found in different tissues and eggs of the loggerhead sea turtle and evaluated the potential ecotoxicological risk for this important species. Eighteen heavy metal elements were determined in different tissues (liver, gonads, fat, kidney, heart, brain, and spleen) of nine individuals of Caretta caretta found stranded along the coasts of Messina (Sicily, Italy) and in the shell and yolk of six eggs from the island of Linosa (Sicily, Italy). For the analysis of the heavy metals, we used the analytical procedures in accordance with the EPA 200.8 method supplemented by EPA 6020b with three replicates for each measurement. The elements analysed showed different organotropism even if the liver showed higher levels of bioaccumulation. Turtles’ tissues showed the highest values of iron in the liver, followed by zinc in the heart and arsenic in the kidney. Regarding eggs, zinc, iron, and barium were dominant in the yolk and iron, boron, and copper in the eggshell. From the analyses carried out the worrying levels of arsenic and cadmium in the kidneys and liver of C. caretta raise questions about the risk related to exposure to these non-essential elements. This study highlights the importance of multi-element biomonitoring by increasing knowledge on the biodistribution of 18 heavy metals and the related potential risks for C. caretta. We also exploring for the first time the presence of several heavy metals in the eggs and their possible implication for the survival of the species

Outcomes of major complications after robotic anatomic pulmonary resection.

BACKGROUND: There is a paucity of robust clinical data on major postoperative complications following robotic-assisted resection for primary lung cancer. This study assessed the incidence and outcomes of patients who experienced major complications after robotic anatomic pulmonary resection. METHODS: This was a multicenter, retrospective review of patients who underwent robotic anatomic pulmonary resection between 2002 and 2018. Major complications were defined as grade III or higher complications according to the Clavien-Dindo classification. Statistical analysis was performed based on patient-, surgeon-, and treatment-related factors. RESULTS: During the study period, 1264 patients underwent robotic anatomic pulmonary resections, and 64 major complications occurred in 54 patients (4.3%). Univariate analysis identified male sex, forced expiratory volume in 1 second, diffusion capacity of the lung for carbon monoxide, neoadjuvant therapy, and extent of resection as associated with increased likelihood of a major postoperative complication. Patient age, performance status, body mass index, reoperation status, and surgeon experience did not have a significant impact on major complications. Patients who experienced at least 1 major complication were at higher risk for an intensive care unit stay of \u3e24 hours (17.0% vs 1.4%; P \u3c .001) and prolonged hospitalization (8.5 days vs 4 days; P \u3c .001). Patients who experienced a major postoperative complication had a 14.8% risk of postoperative death. CONCLUSIONS: In this series, the major complication rate during the postoperative period was 4.3%. A number of identified patient- and treatment-related factors were associated with an increased risk of major complications. Major complications had a significant impact on mortality and duration of stay

Impact of pulmonary function on pulmonary complications after robotic-assisted thoracoscopic lobectomy.

OBJECTIVES: Percentage-predicted forced expiratory volume in 1 s (FEV1) and diffusing capacity for carbon monoxide (DLCO), and their predicted postoperative (ppo) values are established prognostic factors for postoperative pulmonary complications after thoracotomy. However, their predictive value for minimally invasive pulmonary resections remains controversial. This study assessed the incidence of pulmonary complications after robotic lobectomy for primary lung cancer and analysed the predictive significance of FEV1 and DLCO. METHODS: This was a retrospective analysis of patients who underwent robotic lobectomy from 4 institutions. Descriptive and comparative analyses were performed for patients who experienced pulmonary complications versus patients who did not, in relation to FEV1 and DLCO values. To identify thresholds for increased complications, patients were categorized into groups of 10% incremental increases in FEV1 and DLCO, and their ppo values. RESULTS: From November 2002 to April 2018, 1088 patients underwent robotic lobectomy. Overall, 169 postoperative pulmonary complications occurred in 141 patients. Male gender and Eastern Cooperative Oncology Group grade ≥1 were associated with increased pulmonary complications on univariable analysis. Patients who experienced pulmonary complications had increased mortality (2.1% vs 0.2%, P = 0.017) and longer hospitalizations (9 vs 4 days, P \u3c 0.001). Pulmonary complications were associated when FEV1 ≤60% and DLCO ≤50%, and when ppo FEV1 or DLCO was ≤50%; ppo FEV1 ≤50% (P \u3c 0.001) and ppo DLCO ≤50% (P = 0.031) remained statistically significant on multivariable analysis. CONCLUSIONS: Both FEV1 and DLCO were shown to be significant predictors of pulmonary complications. Furthermore, thresholds of percentage-predicted and ppo FEV1 and DLCO values were identified, below which pulmonary complications occurred significantly more frequently, suggesting their predictive values are particularly useful in patients with poorer pulmonary function

First series of total robotic hysterectomy (TRH) using new integrated table motion for the da Vinci Xi: feasibility, safety and efficacy

BACKGROUND: To present the first case series of total robotic hysterectomy (TRH), using integrated table motion (ITM), which is a new feature comprising a unique operating table by Trumpf Medical that communicates wirelessly with the da Vinci Xi surgical system. ITM has been specifically developed to improve multiquadrant robotic surgery such as that conducted in colorectal surgery. METHODS: Between May and October 2015, a prospective post-market study was conducted on ITM in the EU in 40 cases from different specialties. The gynecological study group comprised 12 patients. Primary endpoints were ITM feasibility, safety and efficacy. RESULTS: Ten patients underwent TRH. Mean number of ITM moves was three during TRH; there were 31 instances of table moves in the ten procedures. Twenty-eight of 31 ITM moves were made to gain internal exposure. The endoscope remained inserted during 29 of the 31 table movements (94%), while the instruments remained inserted during 27 of the 31 moves (87%). No external instrument collisions or other problems related to the operating table were noted. There were no ITM safety-related observations and no adverse events. CONCLUSIONS: This preliminary study demonstrated the feasibility, safety and efficacy of ITM for the da Vinci Xi surgical system in TRH. ITM was safe, with no adverse events related to its use. Further studies will be useful to define the real role and potential benefit of ITM in gynecological surgery.