Debate is around the optimal immunization regimen for cancer vaccines since too intense vaccination schedules may exhaust reactive lymphocytes. GX301 is a telomerase-based cancer vaccine whose safety ...and immunological effects were tested in a phase I trial applying an eight administrations schedule. Main objective of this study was to comparatively analyse safety and immunological response to three GX301 regimens in metastatic castration-resistant prostate cancer patients with response/disease stability after docetaxel chemotherapy. This was a multicentre, randomized, parallel-group, open-label trial registered with EudraCT (2014-000095-26) and ClinicalTrials.gov (NCT02293707, 2014). Ninety-eight patients were randomized to receive either eight (regimen 1), four (regimen 2) or two (regimen 3) vaccine administrations. Sixty-three patients were assessable for the primary immunological end-point. Vaccine-specific immune responses were evaluated by intracellular staining for IFN, elispot and cytotoxic assay at 90 and 180 days from baseline. No major side effects were recorded. A 54% overall immune responder rate was observed with 95% of patients showing at least one vaccine-specific immune response. Rate of immunological responders and number of immunizations were proportionally related, suggesting superiority of regimens 1 and 2 over regimen 3. Overall survival did not differ among regimens in both immunological responders and non-responders and was inversely associated (
P
= 0.002) with increase in the number of circulating CD8 + T regulatory cells at 180 days. These data indicate that GX301 cancer vaccine is safe and immunogenic in metastatic castration-resistant prostate cancer patients. Schedules with high number of administrations should be preferred in future studies due to their better immunological outcome.
A series of 5H-dibenzb, fazepine derivatives was prepared and evaluated for binding affinities to muscarinic receptors in vitro. Among them, compound 8 showed a high affinity for human recombinant M2 ...receptors (Ki=2.6 nM), a low affinity for M4 receptors (39-fold less than for M2 receptors) and a very low affinity for M1 and M3 receptors (119- and 112-fold less than for M2 receptors, respectively). The high M2 selectivity of 8 may be attributed to the olefinic bond of the azepine ring. Functional experiments showed 8 to be a competitive antagonist with high affinity to the cardiac (pA2=7.1) and low affinity to the intestinal muscarinic receptors (IC50=0.54 μM). In vivo experiments confirmed the in vitro M2 selectivity of 8. Acetylcholine-induced bradycardia was dose-dependently antagonized in rats after both intravenous and intraduodenal administration of 8. In rats, cholinergic functions mediated by M1 or M3 receptors (salivary secretion, pupil diameter, gastric emptying, intestinal transit time) were not affected by the oral administration of 8 even at doses as high as 30 times the antibradycardic effective dose. Furthermore, 8 had no analgesic activity in mice, indicating poor central nervous system penetration. In dogs, nocturnal bradycardia was dose-dependently inhibited by the oral route with a duration of action of about 24 h. Compound 8 appears to be a promising cardioselective antimuscarinic agent for the treatment of dysfunctions of the cardiac conduction system such as sinus or nodal bradycardia ("sick-sinus syndrome") and atrioventricular block.
Peptide
540-548
, peptide
611-626
, peptide
672-686
and peptide
766-780
, which are derived from human telomerase, constitute the immunogenic component of the GX301 cancer vaccine. The relative ...immunogenicity of these peptides is unknown, thus it is unsure whether their combined use offers real advantages over single peptide stimulation. Hence, this study compared the number of specific immune responses and responders to each peptide, as well as to their mixture (meaning the co-presence of the 4 peptides in the same culture well), achieved after ex vivo stimulation of PBMC from 21, HLA-A2+ (n.11) or HLA-A2- (n.10), healthy donors. The study was performed on freshly collected PBMC (T0) and on PBMC stimulated for 10 d with single peptides or their mixture (T1). Peptide-specific immune responses were analyzed by Elispot and cytokine intracellular staining by flow cytometry. The results showed that each peptide induced specific immune responses in some subjects, with different panels of responders among the peptides. Moreover, the numbers of responses and responders to the single peptides or their mixture were comparable. Importantly, the overall number of responders to the 4 peptides was higher than to each single peptide, or to their mixture, both at T0 and T1. These data demonstrate the immunogenicity of each of the 4 GX301 telomerase peptides. Moreover, they show the advantage of multi-peptide over single peptide stimulation, providing a clear support to their combined administration in vaccination protocols. However, the data pose a warning against peptide administration as a mixture due to possible interference phenomena during antigen presentation processes.
The 5-{4-4-(diethylamino)butyl-1-piperidinyl}acetyl-5
H-dibenz
b,
f-azepine (MF 10058) is a new potent and selective muscarinic M
2 receptor antagonist. The hemodynamic effects of MF 10058 were ...investigated in conscious freely moving dogs. Placebo and three doses of MF 10058 (2, 4 and 8 mg/kg) were orally administered according to a randomised four-way crossover design. Heart rate, cardiac conduction times, systolic and diastolic blood pressure were telemetrically recorded for 12–24 h after dosing. After placebo administration, a consistent reduction over time in heart rate was observed during the night-time period (−15%,
P=0.019). MF 10058 administration antagonised the nocturnal bradycardia and shortened QT interval. The effect of the drug reached statistically significance, compared to placebo, with the highest dose of 8 mg/kg (+19% on heart rate,
P=0.013; −4% on QT interval,
P=0.049). The effect on heart rate lasted for the entire 24-h observation period (+16%,
P=0.030). Nocturnal systolic and diastolic blood pressure were not significantly affected by MF 10058. No other signs of peripheral or central cholinergic block were observed at any dose. The results of this study demonstrated that oral administration of MF 10058 produces long-lasting hemodynamic effects in the conscious dog. The drug has a therapeutic potential for the treatment of bradycardic disorders.
The only therapeutic drugs for combating dementia disease are acetylcholine esterase inhibitors (AChEI). However, the use of tacrine, the first AChEI to be launched as an Alzheimer's disease (AD) ...drug, has been limited by serious side effects. Therefore, efforts to search for more potent and selective inhibitors of AChE still remain highly significant in the therapeutic treatment of AD. In this work we modified the cyclohexyl ring of velnacrine, a less toxic analogue of tacrine, by synthesizing a series of thiopyranoquinolines in which the C-3 methylene unit was replaced by a sulphur atom. The anti-AChE data show that the activity was maintained with the bioisosteric substitution carried out. The introduction of a chlorine atom at different positions of the aromatic ring resulted in an array of different activities. In an attempt to understand the different behaviours displayed by the chlorine-substituted derivatives, a molecular docking study was performed.
The integration of 2D materials in triboelectric nanogenerators (TENGs) is known to increase the mechanical‐to‐electrical power conversion efficiency. 2D materials are used in TENGs with multiple ...roles as triboelectric material, charge‐trapping fillers, or as electrodes. Here, novel TENGs based on few‐layers graphene (FLG) electrodes and stable gel electrolytes composed of liquid phase exfoliated 2D‐transition metal dichalcogenides and polyvinyl alcohol are developed. TENGs embedding FLG and gel composites show competitive open‐circuit voltage (≈ 300 V), instant peak power (530 mW m−2), and stability (> 11 months). These values correspond to a seven‐fold higher electrical output compared to TENGs embedding bare FLG electrodes. It is demonstrated that such a significant improvement depends on the high electrical double‐layer capacitance (EDLC) of FLG electrodes functionalized with the gel composites. The wet encapsulation of the TENGs is shown to be an effective strategy to increase their power output further highlighting the EDLC role. It is also shown that the EDLC is dependent upon the transition metal (W vs Mo) rather than the relative abundance of 1T or 2H phases. Overall, this work lays down the roots for novel sustainable electrochemical‐(e)‐TENGs developed exploiting strategies typically used in electrochemical capacitors.
The fundamental role played by the electrical double‐layer capacitance (EDLC) of few layers graphene (FLG)‐electrodes, in rising the electrical power output of triboelectric nanogenerators (TENGs, 530 mW m−2) is unveiled. Highly capacitive FLG electrodes are obtained by integrating electrolyte gel composites based on 2D‐transition metal dichalcogenides. This work introduces a novel design concept leading to sustainable electrochemical‐TENGs.
Introduction
Intra-abdominal abscesses complicating Crohn’s disease (CD) present an additional challenge as their presence can contraindicate immunosuppressive treatment whilst emergency surgery is ...associated with high stoma rate and complications. Treatment options include a conservative approach, percutaneous drainage, and surgical intervention. The current multicentre study audited the short-term outcomes of patients who underwent preoperative radiological drainage of intra-abdominal abscesses up to 6 weeks prior to surgery for ileocolonic CD.
Methods
This is a retrospective, multicentre, observational study promoted by the Italian Society of Colorectal Surgery (SICCR), including all adults undergoing ileocolic resection for primary or recurrent CD from June 2018 to May 2019. The outcomes of patients who underwent radiological guided drainage prior to ileocolonic resection were compared to the patients who did not require preoperative drainage. Postoperative morbidity within 30 days of surgery was the primary endpoint. Postoperative length of hospital stay (LOS) and anastomotic leak rate were the secondary outcomes.
Results
Amongst a group of 575 included patients who had an ileocolic resection for CD, there were 36 patients (6.2%) who underwent abscess drainage prior to surgery. Postoperative morbidity (44.4%) and anastomotic leak (11.1%) were significantly higher in the group of patients who underwent preoperative drainage.
Conclusions
Patients with Crohn’s disease who require preoperative radiological guided drainage of intra-abdominal abscesses are at increased risk of postoperative morbidity and septic complications following ileocaecal or re-do ileocolic resection.
Introduction
Single-incision laparoscopic surgery (SILS) aims to minimize the surgical access trauma by reducing the number of abdominal incisions to a single site, potentially offering better ...cosmetic results and decreased postoperative pain. In this study, we compare the results of SILS ileocolic resection for Crohn’s disease (CD) to conventional laparoscopy and open surgery using a propensity score–matched analysis in a retrospective national multicentre study.
Methods
All consecutive patients undergoing elective SILS ileocaecal or redo ileocolic resection for primary and recurrent CD from 1 June 2018 to 31 May 2019 were included. Patients were matched 1:1:1 with laparoscopy and open surgery according to perianal disease, recurrent disease, penetrating phenotype of CD, history of previous abdominal surgery, preoperative medical treatment with steroids and anti-TNF. Postoperative morbidity within 30 days of surgery was the primary endpoint.
Results
Fifty-eight patients were included in each group, for a total of 174 patients. The conversion rate for SILS and laparoscopy was 10.3% and 12%, respectively, with no difference in the incidence of postoperative complications (13.8% and 12%,
p
= 0.77), whilst open surgery demonstrated a worse morbidity profile, with a complication rate of 25.9% (
p
< 0.0001). Median length of hospital stay following SILS ileocolic resection was 5 days, significantly shorter compared to 7 days for laparoscopy and 9 for open surgery (
p
< 0.0001).
Conclusions
SILS ileocolonic resection for CD demonstrated a comparable morbidity profile compared to laparoscopy in selected patients, with a reduced length of postoperative hospital stay.