Gastrin and cholecystokinin peptide-based radiopharmaceuticals: an in vivo and in vitro comparison

The development of suitable radioligands for targeting CCK-2 receptor expressing tumors, such as medullary thyroid carcinoma, is of great clinical interest. In the search for the best CCK-2R binding peptides, we have synthesized, evaluated and compared the CCK8 peptide (Asp-Tyr-Met-Gly-Trp-Met-Asp-PheNH(2) ) and two gastrin analogs commonly referred to as MG0 (DGlu-Glu(5)-Ala-Tyr-Gly-Trp-Met-Asp-PheNH(2) ) and MG11 (DGlu(1)-Ala-Tyr-Gly-Trp-Met-Asp-PheNH(2) ). The N-terminal portion of the three peptide sequences was derivatized by introducing the DTPAGlu or DOTA chelators to allow radiolobeling with (111) In(III) and (68) Ga(III), respectively. Saturation binding and cellular internalization experiments were performed on A431 cells overexpressing CCK2R (A431-CCK2R). All compounds showed Kd values in the nM range and were internalized with similar rates in CCK2 receptor overexpressing cells. Biodistribution experiments showed higher specific uptake of both MG0-based compounds compared to conjugates containing the CCK8 and MG11 peptide sequences. The higher retention levels of MG0-based peptides were associated with markedly elevated and undesired kidney uptake compared to the other compounds. Current indications suggest that the 5 Glu N-terminal residues while improving peptide stability and receptor-mediated tumor uptake cause unacceptably high kidney retention. Although displaying lower absolute tumor uptake values, the DOTA-coupled CCK8 peptide provided the best tumor to kidney uptake ratio and appears more suitable as lead compound for improvement of radiopharmaceutical properties

The [Tc(N)(PNP)]2+ metal fragment labeled cholecystokinin-8 (CCK8) peptide for CCK-2 receptors imaging: in vitroand in vivo studies

The radiolabeling of the natural octapeptide CCK8, derivatized with a cysteine residue (Cys-Gly-CCK8), by using the metal fragment [99mTc(N)(PNP3)]2+ (PNP3 = N,N-bis(dimethoxypropylphosphinoethyl)methoxyethylamine) is reported. The [99mTc(N)(NS-Cys-Gly-CCK8)(PNP3)]+ complex was obtained according to two methods (one-step or two-step procedure) that gave the desired compound in high yield. The complex is stable in aqueous solution and in phosphate buffer. In vitro challenge experiments with an excess of cysteine and glutathione indicate that no transchelation reactions occur, confirming the high thermodynamic stability and kinetic inertness of this compound. Stability studies carried out in human and mouse serum, as well as in mouse liver homogenates, show that the radiolabeled compound remains intact for prolonged incubation at 37 degrees C. Binding properties give Kd (19.0 +/- 4.6 nmol/l) and Bmax (approximately 10(6) sites/cell) values in A431 cells overexpressing the CCK2-R. In vivo evaluation of the compound shows rapid and specific targeting to CCK2-R, a fourfold higher accumulation compared to nonreceptor expressing tumors

A study of gas contaminants and interaction with materials in RPC closed loop systems

Resistive Plate Counters (RPC) detectors at the Large Hadron Collider (LHC) experiments use gas recirculation systems to cope with large gas mixture volumes and costs. In this paper a long-term systematic study about gas purifiers, gas contaminants and detector performance is discussed. The study aims at measuring the lifetime of purifiers with unused and used cartridge material along with contaminants release in the gas system. During the data-taking the response of several RPC double-gap detectors was monitored in order to characterize the correlation between dark currents, filter status and gas contaminants

Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

Ceftolozane/tazobactam for resistant drugs pseudomonas aeruginosa respiratory infections: A systematic literature review of the real-world evidence

Background: Ceftolozane/tazobactam (C/T) is a β-lactam/β-lactamase inhibitor combination that mainly targets Gram-negative bacteria. The current international guidelines recommend including C/T treatment in the empirical therapy for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). Pseudomonas aeruginosa (PA) is one of the most challenging Gram-negative bacteria. We conducted a systematic review of all cases reported in the literature to summarize the existing evidence. Methods: The main electronic databases were screened to identify case reports of patients with drug-resistant PA respiratory infections treated with C/T. Results: A total of 22 publications were included for a total of 84 infective episodes. The clinical success rate was 72.6% across a wide range of comorbidities. The 45.8% of patients treated with C/T presented colonization by PA. C/T was well tolerated. Only six patients presented adverse events, but none had to stop treatment. The most common therapeutic regimens were 1.5 g every 8 h and 3 g every 8 h. Conclusion: C/T may be a valid therapeutic option to treat multidrug-resistant (MDR), extensively drug-resistant (XDR), pandrug-resistant (PDR), and carbapenem-resistant (CR) PA infections. However, further data are necessary to define the optimal treatment dosage and duration

Driving pressure during general anesthesia for open abdominal surgery (DESIGNATION) : study protocol of a randomized clinical trial

Background Intraoperative driving pressure (Delta P) is associated with development of postoperative pulmonary complications (PPC). When tidal volume (V-T) is kept constant, Delta P may change according to positive end-expiratory pressure (PEEP)-induced changes in lung aeration. Delta P may decrease if PEEP leads to a recruitment of collapsed lung tissue but will increase if PEEP mainly causes pulmonary overdistension. This study tests the hypothesis that individualized high PEEP, when compared to fixed low PEEP, protects against PPC in patients undergoing open abdominal surgery. Methods The "Driving prESsure durIng GeNeral AnesThesIa for Open abdomiNal surgery trial" (DESIGNATION) is an international, multicenter, two-group, double-blind randomized clinical superiority trial. A total of 1468 patients will be randomly assigned to one of the two intraoperative ventilation strategies. Investigators screen patients aged >= 18 years and with a body mass index <= 40 kg/m(2), scheduled for open abdominal surgery and at risk for PPC. Patients either receive an intraoperative ventilation strategy with individualized high PEEP with recruitment maneuvers (RM) ("individualized high PEEP") or one in which PEEP of 5 cm H2O without RM is used ("low PEEP"). In the "individualized high PEEP" group, PEEP is set at the level at which Delta P is lowest. In both groups of the trial, V-T is kept at 8 mL/kg predicted body weight. The primary endpoint is the occurrence of PPC, recorded as a collapsed composite of adverse pulmonary events. Discussion DESIGNATION will be the first randomized clinical trial that is adequately powered to compare the effects of individualized high PEEP with RM versus fixed low PEEP without RM on the occurrence of PPC after open abdominal surgery. The results of DESIGNATION will support anesthesiologists in their decisions regarding PEEP settings during open abdominal surgery

Comparison of two rocuronium bromide doses in adult and elderly patients who underwent laparoscopic surgery

Background The aim of our study was to evaluate the effects of two different doses of rocuronium bromide (0.5 mg/kg and 0.9 mg/kg) on the length of neuromuscular block, on the haemodynamic stability and on the side effects in patients of different ages. Methods We recruited 80 patients who underwent laparoscopic surgery (cholecystectomy, appendicectomy, varicocelectomy) belonging to ASA I–II classes and divided them into four groups:• 20 adults (A0.5) who received rocuronium bromide 0.5 mg/kg• 20 elderly patients (E0.5) who received rocuronium bromide 0.5 mg/kg• 20 adults (A0.9) who received rocuronium bromide 0.9 mg/kg• 20 elderly patients (E0.9) who received rocuronium bromide 0.9 mg/kgIntubation conditions, continuous monitoring of HR, NIBP, SpO2, EtCO2 were recorded. Onset time, REC 25%, TOF-ratio 0.70 were analysed by TOF-WATCH.Nerve-evoked muscle tension and neuromuscular paralysis extension were expressed by strength of contraction of adductor pollicis, in response to a direct stimulation of the ulnar nerve (TOF). Results The results showed that in elderly patients the effect of rocuronium bromide, at two different doses, was similar. Significant differences regarding the onset time was found among the groups showing that with the same dose of rocuronium bromide, the onset time was prolonged in elderly patients compared to adult patients. Moreover, increasing the dose, the onset time was reduced in both groups (p < 0.05). Forty per cent of adult group A0.5 showed excellent intubation conditions versus 60% of A0.9 (p < 0.05); elderly patients did not show any significant difference in the intubation procedure after different doses of rocuronium bromide.ConclusionsThe results from the four groups showed that in elderly patients 0.5 mg/kg of rocuronium bromide resulted in a good recovery, while 0.9 mg/kg increased the recovery time. Moreover, in adults the high dose was more effective because it reduced the number of injections and post-operative recovery time

Rubella Immunity among Italian Female Healthcare Workers: A Serological Study

Rubella, also known as German measles or three-day measles, is an infectious disease caused by virus of the genus Rubivirus, which may be prevented by vaccination. The infection is potentially dangerous for non immune subjects, although 20–50% of infected subjects are asymptomatic. Healthcare workers (HCWs) have an increased potential exposure to rubella in comparison to the general population, putting them and their patients at risk of infection and its complications. In 2019, 20 cases of rubella have been reported in Italy. According to the Italian National Immunization and Prevention Plan, HCWs should provide a written certification of vaccination for rubella or serological evidence of protective antibodies. The aim of the study was to evaluate the rubella immunization status in female HCWs of the teaching hospital Policlinic Rome Tor Vergata (PTV) of childbearing age. For this purpose, we retrospectively checked the serologic values of rubella-specific IgG antibodies analyzing the clinical records of the HCWs of undergoing the occupational health surveillance program from January 1st to June1st 2020. Five hundred fourteen HCWs with a mean age of 23.19 (range 19–37, DS: 2.80) were included: 90.3% (464) showed a protective antibody titre. The mean value of the anti-rubella IgG was 49.59 IU/mL. Our study shows a non-protective anti rubella IgG titre in a substantial percentage of HCWs (9.7%). As vaccine protection decreases over the years and the risk of congenital rubella syndrome (CRS) in vaccinated subjects should not be underestimated, we suggest routine screening of the immunological status followed by the administration of a third dose of vaccine if the antibody titre becomes non-protective