Comparison of in vitro and in vivo biological effects of trabectedin,lurbinectedin (PM01183) and Zalypsis® (PM00104)

This study: (i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared with trabectedin in cell lines deficient in specific mechanisms of repair, (ii) evaluated their in vivo antitumor activity against a series of murine tumors and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumor lines were very similar. Nucleotide Excision Repair (NER) deficient cells were approximately fourfold more resistant to trabectedin, lurbinectedin and Zalypsis®. Cells deficient in non‐homologous end joining (NHEJ), MRN complex and translesion synthesis (TLS) were slightly more sensitive to the three compounds (approximately fivefold) while cells deficient in homologous recombination (HR) were markedly more sensitive (150–200‐fold). All three compounds showed a good antitumor activity in several in vivo models. Lurbinectedin and trabectedin had a similar pattern of antitumor activity in murine tumors and in xenografts, whereas Zalypsis® appeared to have a distinct spectrum of activity. The fact that no relationship whatsoever was found between the in vitro cytotoxic potency and the in vivo antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host‐mediated effects are involved in the in vivo pharmacological effects.     

Current perspectives in therapeutic myocardial angiogenesis

The complex mechanisms mediating the development of new blood vessels are now beginning to be unraveled. In conjunction with major biotechnology advances, this has facilitated the initiation of translational research related to a novel treatment strategy for patients with myocardial or leg ischemia due to obstructive arterial disease--therapeutic angiogenesis. At present, at least 17 clinical trials of myocardial angiogenesis have been presented involving over 900 patients. Uncertainty exists as to the optimal delivery route and angiogenic agent, and this uncertainty is reflected in the diverse methodology of the trials published thus far. The majority of patients received an angiogenic protein via the intracoronary route. Other delivery techniques--such as direct intramyocardial injection via transepicardial or transendocardial routes--and other angiogenic agents, including master genes, have also been studied. Most recently, interest has grown in the potential angiogenesis effects of cell therapy--such as autologous bone marrow cells or cultured stem cells--and there are now several groups initiating Phase I/II trials in this area. This review summarizes the current evidence pertaining to the safety, feasibility, and efficacy of various angiogenic techniques aimed at enhancing myocardial blood flow and alleviating angina.     

Prediction of clinical outcomes in Crohn’s disease by using confocal laser endomicroscopy: results from a prospective multicenter study

1. Download high-res image (274KB)
2. Download full-size image

     

Permanent-temporary pacemakers in the management of patients with conduction abnormalities after transcatheter aortic valve replacement

Background

Damage to the cardiac conduction system requiring permanent pacemaker (PPM) implantation is a known adverse outcome of transcatheter aortic valve replacement (TAVR). A permanent-temporary pacemaker (PTPM) is a device that involves an active-fixation lead attached to an external pulse generator taped to the skin. We reviewed the utility of PTPMs as a temporary bridge measure after TAVR in patients with conduction abnormalities that do not meet conventional criteria for PPM placement.

Methods

Between January 01, 2013 and December 31, 2015, we analyzed 67 patients who received PTPM after TAVR. Baseline demographics, comorbidities, type and size of the valve, pre-TAVR electrocardiograms (ECGs), post-TAVR ECGs at 1 day, 1 month, and 6 months, and pacemaker interrogation results were reviewed for each patient if available.

Results

The mean age of patients was 80.5?±?9.1 years. PTPM were placed for 2.3?±?2.4 days. Among these patients, 44.8% (n?=?30) received a PPM prior to discharge. Male gender (OR 2.84, 95% CI 1.05–7.69, p?=?0.05) and an increase in QRS duration post-TAVR (p?=?0.01) were associated with PPM placement. Pacemaker interrogation data of 11 patients with PPM revealed that 27% (n?=?3) had <?1% V-pacing requirements and <?10% A-pacing requirements.

Conclusions

In post-TAVR patients who develop conduction abnormalities that do not meet conventional PPM implantation indications, PTPM safely provides a time period for further assessment and may prevent unnecessary PPM implantation. Male gender and an increase in QRS duration post-TAVR are associated with PPM implantation. Additionally, some patients may recover from their conduction disturbances and demonstrate low pacemaker utilization.

     

Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome

MED13L haploinsufficiency has recently been described as responsible for syndromic intellectual disability. We planned a search for causative gene variants in seven subjects with intellectual disability and overlapping dysmorphic facial features such as bulbous nasal tip, short mouth and straight eyebrows. We found two de novo frameshift variants in MED13L, consisting in single-nucleotide deletion (c.3765delC) and duplication (c.607dupT). A de novo nonsense variant (c.4420A>T) in MED13L was detected in a further subject in the course of routine whole-exome sequencing. By analyzing the clinical data of our patients along with those recently described in the literature, we confirm that there is a common, recognizable phenotype associated with MED13L haploinsufficiency, which includes intellectual disability and a distinctive facial appearance. Congenital heart diseases are found in some subjects with various degree of severity. Our observation of cleft palate, ataxia, epilepsy and childhood leukemia observed in single cases broadens the known clinical spectrum. Haploinsufficiency for MED13L should be considered in the differential diagnosis of the 1p36 microdeletion syndrome, due to overlapping dysmorphic facial features in some patients. The introduction of massive parallel-sequencing techniques into clinical practice is expected to allow for detection of other causative point variants in MED13L. Analysis of genomic data in connection with deep clinical evaluation of patients could elucidate genetic heterogeneity of the MED13L haploinsufficiency phenotype.