A novel temporary atrioventricular sequential pacing catheter-Characteristics and first-in-human application.

BACKGROUND: Sequential synchronized atrioventricular (AV) pacing provides enhanced electrophysiologic parameters which contribute to improved hemodynamic parameters and increased cardiac performance to subsequently confer a clinical advantage over traditional ventricular pacing. Current temporary transvenous pacemaker catheters are limited to only one electrode which paces solely the right ventricle, thus lacking the capability to provide the optimal pacing mode. A new multilead pacemaker device was developed in response to the need for improved temporary pacing through the utilization of sequential synchronized atrioventricular pacing (TAVSP). It consists of seven preformed, preshaped nitinol wires electrodes, of which four are for intra-atrial and three for intraventricular positioning and endocardial contact, respectively. Each wire carries a ball tip designed to minimize tissue trauma and provide a high current density for adequate myocardial capture. The device is not yet Food and Drug Administration approved. OBJECTIVE: To present the unique structural components and mechanical properties of a novel sequential synchronized AV pacing device for temporary insertion and to report its first-in-human application with an analysis of the early clinical experience. METHODS: Following a process of development and proof of concept of the novel pacing modality in an animal model which demonstrated feasibility and safety, a series of patients who were candidates for the device application was identified. During left and right heart catheterization, the novel temporary pacing catheter was inserted transvenously and delivered in most patients under fluoroscopy or echocardiography. The catheter was deployed to its target right heart anatomic sites and then activated in an AV sequential mode. The technical aspects, the corresponding clinical utilization, and device performance were documented and analyzed. RESULTS: The series included 10 enrolled subjects. During planned left and right heart catheterization, the novel TAVSP device was inserted transvenously and then delivered and deployed successfully in a timely fashion in all patients. The pacing catheter achieved proper threshold and impedance in all (100%) patients. The performance of all ventricular leads was adequate; however, in 1 (10%) patient poor performance of the atrial leads was detected. The device was successfully retrieved in all patients. No adverse arrhythmia, impaired hemodynamics, or clinical adverse events occurred. No technical difficulties, component failure, or wires thrombosis were detected. All patients sustained the device application without sequala and were discharged home. CONCLUSION: Initial clinical experience with the utilization of a novel TAVSP demonstrates feasibility and safety in humans. The TAVSP modality potentially offers improved pacing capability and subsequent hemodynamic benefits over the current temporary pacing catheters. Further experience with the clinical application of this pacing catheter is warranted.

Severe Right Ventricular Failure Following Pericardiocentesis: A Case Report of Pericardial Decompression Syndrome.

Pericardial decompression syndrome, a rare but potentially fatal complication following pericardiocentesis, is defined as paradoxical hemodynamic deterioration. The exact pathophysiology is unknown, but it is likely that several mechanisms involving hemodynamic, ischemic, and autonomic imbalance play a role. There is no specific treatment; however, early supportive interventions should be implemented. (Level of Difficulty: Intermediate.).

p-Cymene Complexes of Ruthenium(II) as Antitumor Agents.

In this work, the cytotoxic behavior of six ruthenium(II) complexes of stoichiometry [(η6-p-cymene)RuCl2L] (I-VI), L = 4-cyanopyridine (I), 2-aminophenol (II), 4-aminophenol (III), pyridazine (IV), and [(η6-p-cymene)RuClL2]PF6; L = cyanopyridine (V), L = 2-aminophenol(VI) towards three cell lines was studied. Two of them, HeLa and MCF-7, are human carcinogenic cells from cervical carcinoma and human breast cancer, respectively. A comparison with healthy cells was carried out with BGM cells which are monkey epithelial cells of renal origin. The behavior of complex II exhibits selectivity towards healthy cells, which is a promising feature for use in cancer treatment since it might reduce the side effects of most current therapies.

Folate deficiency prevents neural crest fate by disturbing the epigenetic Sox2 repression on the dorsal neural tube.

Folate deficiency has been known to contribute to neural tube and neural crest defects, but why these tissues are particularly affected, and which are the molecular mechanisms involved in those abnormalities are important human health questions that remain unanswered. Here we study the function of two of the main folate transporters, FolR1 and Rfc1, which are robustly expressed in these tissues. Folate is the precursor of S-adenosylmethionine, which is the main donor for DNA, protein and RNA methylation. Our results show that knockdown of FolR1 and/or Rfc1 reduced the abundance of histone H3 lysine and DNA methylation, two epigenetic modifications that play an important role during neural and neural crest development. Additionally, by knocking down folate transporter or pharmacologically inhibiting folate transport and metabolism, we observed ectopic Sox2 expression at the expense of neural crest markers in the dorsal neural tube. This is correlated with neural crest associated defects, with particular impact on orofacial formation. By using bisulfite sequencing, we show that this phenotype is consequence of reduced DNA methylation on the Sox2 locus at the dorsal neural tube, which can be rescued by the addition of folinic acid. Taken together, our in vivo results reveal the importance of folate as a source of the methyl groups necessary for the establishment of the correct epigenetic marks during neural and neural crest fate-restriction.

New Acridine Thiourea Gold(I) Anticancer Agents: Targeting the Nucleus and Inhibiting Vasculogenic Mimicry.

Two new 1-acridin-9-yl-3-methylthiourea Au(I) DNA intercalators [Au(ACRTU)2]Cl (2) and [Au(ACRTU) (PPh3)]PF6 (3) have been prepared. Both complexes were highly active in the human ovarian carcinoma cisplatin-sensitive A2780 cell line, exhibiting IC50 values in the submicromolar range. Compounds 2 and 3 are also cytotoxic toward different phenotypes of breast cancer cell lines MDA-MB-231 (triple negative), SK-BR-3 (HER2+, ERα-, and ERß-), and MCF-7 (ER+). Both complexes induce apoptosis through activation of caspase-3 in vitro. While inhibition of some proteins (thiol-containing enzymes) seems to be the main mechanism of action for cytotoxic gold complexes, 2 and 3 present a DNA-dependent mechanism of action. They locate in the cell nucleus according to confocal microscopy and transmission electronic microscopy. The binding to DNA resulted to be via intercalation as shown by spectroscopic methods and viscometry, exhibiting a dose-dependent response on topoisomerase I mediated DNA unwinding. In addition, 2 and 3 exhibit potent antiangiogenic effects and are also able to inhibit vasculogenic mimicry of highly invasive MDA-MB-231 cells.

Exploring the Influence of the Aromaticity on the Anticancer and Antivascular Activities of Organoplatinum(II) Complexes.

A series of new organometallic PtII complexes of the type [Pt(C^N)Cl(DMSO)] (C^N=N,N-dimethyl-1-(2-aryl)methanamine-κ2 C2,N; aryl=phenyl 2 a, biphenyl 2 b, p-terphenyl 2 c, naphthyl 2 d, anthracenyl 2 e, or pyrenyl 2 f) have been synthesized to explore the influence of the aromaticity on their anticancer activity. The best performers, 2 b and d, are more active than cisplatin (CDDP) in epithelial ovarian carcinoma cells A2780, with 2 d having a higher selectivity factor than CDDP in all the tested cell lines. In addition, all the new compounds overcome the acquired resistance in A2780cisR cells and interestingly, show low micromolar IC50 values towards the triple negative breast cancer cell line MDA-MB-231 and the highly metastatic 518A2 melanoma cells. This study shows that the hydrophobicity, accumulation into cells, and metal levels on nuclear DNA for the complexes are consistent with their cytotoxicity. Complexes 2 b and d induce apoptosis in a caspase-independent manner and suppress the intracellular ROS generation without modifying the mitochondria membrane potential. In addition, 2 a-f effectively inhibit angiogenesis in the endothelial cell line EA.hy926 at sub-cytotoxic concentrations and 2 b and d show in vivo antivascular effects on the chorioallantoic membrane (CAM) of fertilized SPF-eggs (SPF=specific-pathogen-free). Inhibition of tubulin polymerization and degeneration of cytoskeleton organization in 518A2 melanoma cells are presented as a preliminary mechanism of its antimetastatic activity.

Highly potent extranuclear-targeted luminescent iridium(iii) antitumor agents containing benzimidazole-based ligands with a handle for functionalization.

A series of 6 substitutionally inert and luminescent iridium(iii) antitumor agents of the type [Ir(C∧N)2(N∧N)][PF6] containing a benzimidazole N∧N ligand with an ester group as a handle for further functionalization has been prepared. They exhibit IC50 values in the high nanomolar range in some ovarian and breast cancer cell lines (approximately 100× more cytotoxic than cisplatin (CDDP) in MDA-MB-231) and are located in the actin cortex predominantly as shown by confocal luminescence microscopy. This discovery could open the door to a new large family of drug bioconjugates with diverse and simultaneous functions.

Novel C,N-Cyclometalated Benzimidazole Ruthenium(II) and Iridium(III) Complexes as Antitumor and Antiangiogenic Agents: A Structure-Activity Relationship Study.

A series of novel C,N-cyclometalated benzimidazole ruthenium(II) and iridium(III) complexes of the types [(η(6)-p-cymene)RuCl(κ(2)-N,C-L)] and [(η(5)-C5Me5)IrCl(κ(2)-N,C-L)] (HL = methyl 1-butyl-2-arylbenzimidazolecarboxylate) with varying substituents (H, Me, F, CF3, MeO, NO2, and Ph) in the R4 position of the phenyl ring of 2-phenylbenzimidazole chelating ligand of the ruthenium (3a-g) and iridium complexes (4a-g) have been prepared. The cytotoxic activity of the new ruthenium(II) and iridium(III) compounds has been evaluated in a panel of cell lines (A2780, A2780cisR, A427, 5637, LCLC, SISO, and HT29) in order to investigate structure-activity relationships. Phenyl substitution at the R4 position shows increased potency in both Ru and Ir complexes (3g and 4g, respectively) as compared to their parent compounds (3a and 4a) in all cell lines. In general, ruthenium complexes are more active than the corresponding iridium complexes. The new ruthenium and iridium compounds increased caspase-3 activity in A2780 cells, as shown for 3a,d and 4a,d. Compound 4g is able to increase the production of ROS in A2780 cells. Furthermore, all the new compounds are able to overcome the cisplatin resistance in A2780cisR cells. In addition, some of the metal complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926 at 0.5 µM, the ruthenium derivatives 3g (Ph) and 3d (CF3) being the best performers. QC calculations performed on some ruthenium model complexes showed only moderate or slight electron depletion at the phenyl ring of the C,N-cyclometalated ligand and the chlorine atom on increasing the electron withdrawing effect of the R substituent.

Antitumor properties of platinum(iv) prodrug-loaded silk fibroin nanoparticles.

Platinum(iv) complexes take advantage of the exclusive conditions that occur within the tumor to carry out their cytotoxic activity. On the other hand, silk fibroin has natural properties which make it very interesting as a biomaterial: high biocompatibility, biodegradability, low immunogenicity, high cellular penetration capacity and high reactive surface. Herein we report the preparation of silk fibroin nanoparticles (SFNs) loaded with the hydrophobic Pt(iv) complex cis,cis,trans-[Pt(NH(3))(2)Cl(2)(O(2)CC(6)H(5))(2)] (PtBz). Only a small fraction of the loaded PtBz is released (less than 10% after 48 h). PtBz-SFNs trigger strong cytotoxic effects against human ovarian carcinoma A2780 cells and their cisplatin-resistant variant A2780cisR cells. Interestingly, PtBz-SFNs are very cytotoxic (nanomolar IC(50) values) toward the triple negative breast tumor cell line MDA-MB-231, and also toward SK-BR-3 and MCF-7, while maintaining an excellent selectivity index.

Dual antitumor and antiangiogenic activity of organoplatinum(II) complexes.

A library of over 20 cycloplatinated compounds of the type [Pt(dmba-R)LCl] (dmba-R = C,N-dimethylbenzylamine-like ligand; R being MeO, Me, H, Br, F, CF3, and NO2 substituents in the R5 or R4 position of the phenyl ring; L = DMSO and P(C6H4CF3-p)3) has been prepared. All compounds are active in both human ovarian carcinoma A2780 cells and cisplatin-resistant A2780cisR cells, with most of the DMSO platinum complexes exhibiting IC50 values in the submicromolar range in the A2780 cell line. Interestingly, DMSO platinum complexes show low cytotoxicity in the nontumorigenic kidney cell line BGM and therefore high selectivity factors SF. In addition, some of the DMSO platinum complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926. These are the first platinum(II) complexes reported to inhibit angiogenesis at a close concentration to their IC50 in A2780 cells, turning them into dual cytotoxic and antiangiogenic compounds.