Enhanced intraperitoneal delivery of charged, aerosolized curcumin nanoparticles by electrostatic precipitation

Aims: To investigate the potential of curcumin-loaded polylactic-co-glycolic acid nanoparticles (CUR-PLGA-NPs), alone and with electrostatic precipitation, for improving tissue uptake during pressurized intraperitoneal aerosol chemotherapy (PIPAC). Methods: Positively and negatively charged CUR-PLGA-NPs were delivered as PIPAC into inverted bovine urinary bladders ex vivo. The experiment was repeated with the additional use of electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (electrostatic PIPAC). Results: Positively charged CUR-PLGA-NPs increased depth of tissue penetration by 81.5% and tissue concentration by 80%. Electrostatic precipitation further improved the uptake of positively charged CUR-PLGA-NPs by 41.8%. Conclusion: The combination of positive charge and electrostatic precipitation have significant potential to improve tissue uptake of nanoparticles during intraperitoneal chemotherapy

Emphysema and secondary pneumothorax in young adults smoking cannabis

Background: We observed a remarkable increase in the number of young patients who presented with lung emphysema and secondary spontaneous pneumothorax (SSP) at our institution for over a period of 30 months; most of them have a common history of marijuana abuse. Study design: Retrospective case series. Methods: Seventeen young patients presented with spontaneous pneumothorax with bullous lung emphysema were systematically evaluated over a period of 30 months. All were regular marijuana smokers. Clinical history, chest X-ray, CT-scan, lung function test, and laboratory and histological examinations were assessed. We compared the findings of this group (group I) with the findings of non-marijuana smoking patients (group II) in the same period. The findings of this series were also compared with the findings of 75 patients presented with pneumothorax in a previous period from January 2000 till March 2002 (group III). Results: In group I, there were 17 patients: the median age of the patients was 27 years (range 19-43 years), 16 males and 1 female. All were living in Switzerland. All but one smoked marijuana daily for a mean of 8.8 years and tobacco for 11.8 years. CT-scan showed multiple bullae at the apex or significant bullous emphysema with predominance in the upper lobes only in two patients. Only two patients had reduced forced first second expiratory volume (FEV1) and one reduced vital capacity (VC) below the predicted 50%. This correlated with the subjectively asymptomatic condition of the patients. All but two patients were treated by video-assisted thoracoscopic surgery (VATS) for prevention of relapsing pneumothorax. Histology showed severe lung emphysema, inflammation, and heavily pigmented macrophages. In group II, there were 85 patients: there were 78 males, the median age was 24 years (range 17-40 years), 74 patients smoked tobacco for 13.4 years but no marijuana. CT-scan in 72 patients showed only small bullae at the apex but no significant emphysema; other clinical, laboratory, and histopathological findings showed no significant difference in group I. In group III, there were 75 patients: there were 71 males and 4 females. Mean age was 25 years (range 16-46 years). Six smoked marijuana daily for a mean of 3.2 years, and 62 smoked tobacco for 14 years. CT-scan done in 59 patients showed few small bullae at the apex but no significant lung emphysema. The presence of lung emphysema on CT-scan in group I was significantly different than in groups II and III (p = 0.14). No significant difference was found among all groups in the form of clinical, laboratory, and histopathological findings. Conclusions: In case of emphysema in young individuals, marijuana abuse has to be considered in the differential diagnosis. The period of marijuana smoking seems to play an important role in the development of lung emphysema. This obviously quite frequent condition in young and so far asymptomatic patients will have medical, financial, and ethical impact, as some of these patients may be severely handicapped or even become lung transplant candidates in the futur

Intraperitoneal aerosolization of albumin-stabilized paclitaxel nanoparticles (Abraxane™) for peritoneal carcinomatosis : a phase I first-in-human study

Background: Nanoparticles hold considerable promise for aerosol-based intraperitoneal delivery in patients with carcinomatosis. Recently, results from preclinical and early clinical trials suggested that albumin-bound paclitaxel (ABP, Abraxane (TM)) may result in superior efficacy in the treatment of peritoneal metastases (PM) compared to the standard solvent-based paclitaxel formulation (Taxol (TM)). Here, we propose a phase I study of pressurized intraperitoneal aerosol chemotherapy (PIPAC) using ABP in patients with upper Gastrointestinal, breast, or ovarian cancer. Methods: Eligible patients with advanced, biopsy-proven PM from ovarian, breast, gastric, hepatobiliary, or pancreatic origin will undergo three PIPAC treatments using ABP with a 4-week interval. The dose of ABP will be escalated from 35 to 140 mg/m(2) using a Bayesian approach until the maximally tolerated dose is determined. The primary end point is dose-limiting toxicity. Secondary analyses include surgical morbidity, non-access rate, pharmacokinetic and pharmacodynamic analyses, quality of life, and exploratory circulating biomarker analyses. Discussion: ABP holds considerable promise for intraperitoneal aerosol delivery. The aim of this study is to determine the dose level for future randomized phase II trials using ABP in PIPAC therapy

Prominent role of the Ig-like V domain in trans-interactions of nectins. Nectin3 and nectin 4 bind to the predicted C-C'-C"-D beta-strands of the nectin1 V domain.

Nectins form a family of integral molecules that belong to the immunoglobulin superfamily. Their ectodomain is made of three Ig-like domains (V, C, C). This family comprises at least five members, namely nectin1, -2, -3, -4, and poliovirus receptor (PVR), that are involved in different physiological and pathological processes. (i) Nectins are adhesion molecules localized at adherens junctions in epithelial cells. (ii) Some nectins act as poliovirus or alpha-herpesvirus receptors (nectin1). (iii) Nectin1 mutations are involved in orofacial developmental abnormalities in humans. Adhesion properties of nectins are mediated by Ca(2+)-independent homophilic and heterophilic processes through ectodomain trans-interactions. We have described a nectin trans-hetero-interaction network: nectin3 binds to nectin1, nectin2, and PVR; nectin1 also binds to nectin4. In the present study we compared the affinities of the different trans-interactions mediated by nectin1. We found that the K(D) of nectin1/nectin3 and nectin1/nectin4 interactions is 1 and 100 nm, respectively, whereas the K(D) of the nectin1-mediated homophilic interaction is 1 microm. We show that nectin1/nectin3 and nectin1/nectin4 trans-hetero-interactions were mediated through trans V to V domain interactions, whereas C domains contributed to increase the affinity of the interaction. Nectin3 and nectin4 share a common binding region in the nectin1 V domain: (i) nectin3 strongly competed with nectin4 binding, (ii) nectin3 and nectin4 binding to nectin1 was reduced by a number of monoclonal antibodies directed against the nectin1 V domain, and (iii) the glycoprotein D of herpes simplex virus-1 that binds to the V domain of nectin1 reduced nectin3 and nectin4 binding. Finally, using chimeric nectin1/PVR receptors where PVR V domain beta-strands were substituted with the corresponding regions of nectin1, the nectin3 and nectin4 minimal binding region on nectin1 V domain was mapped to the C-C'-C"-D beta-strands

Numerical validation of a new method to assess aortic pulse wave velocity from a single recording of a brachial artery waveform with an occluding cuff

Recently a new method has been proposed as a tool to measure arterial pulse wave velocity (PWV), a measure of the stiffness of the large arteries and an emerging parameter used as indicator of clinical cardiovascular risk. The method is based on measurement of brachial blood pressure during supra-systolic pressure inflation of a simple brachial cuff (the device is known as the Arteriograph (Tensiomed, Budapest, Hungary)). This occlusion yields pronounced first and secondary peaks in the pressure waveform, the latter ascribed to a reflection from the aortic bifurcation, and PWV is calculated as the ratio of twice the jugulum-symphysis distance and the time difference between the two peaks. To test the validity of this working principle we used a numerical model of the arterial tree to simulate pressures and flows in the normal configuration, and in a configuration with an occluded brachial artery. A pronounced secondary peak was indeed found in the brachial pressure signal of the occluded model, but its timing was only related to brachial stiffness and not to aortic stiffness. We also compared PWV’s calculated with 3 different methods: PWVATG (~ Arteriograph principle), PWVcar-fem (~ carotid-femoral PWV, the current clinical gold standard method) and PWVtheor (~ Bramwell-Hill equation). Both PWVATG (R²=0.94) and PWVcar-fem (R²=0.95) correlated well with PWVtheor, but their numerical values were lower (by 2.17 ± 0.42 and 1.08 ± 0.70 m/s for PWVATG and PWVcar-fem, respectively). In conclusion, our simulations question the working principle of the Arteriograph. Our data indicate that the method picks up wave reflection phenomena confined to the brachial artery, and derived values of PWV rather reflect the stiffness of the brachial arteries

DNAM-1 and PVR Regulate Monocyte Migration through Endothelial Junctions

DNAX accessory molecule 1 (DNAM-1; CD226) is a transmembrane glycoprotein involved in T cell and natural killer (NK) cell cytotoxicity. We demonstrated recently that DNAM-1 triggers NK cell–mediated killing of tumor cells upon engagement by its two ligands, poliovirus receptor (PVR; CD155) and Nectin-2 (CD112). In the present paper, we show that PVR and Nectin-2 are expressed at cell junctions on primary vascular endothelial cells. Moreover, the specific binding of a soluble DNAM-1–Fc molecule was detected at endothelial junctions. This binding was almost completely abrogated by anti-PVR monoclonal antibodies (mAbs), but not modified by anti–Nectin-2 mAbs, which demonstrates that PVR is the major DNAM-1 ligand on endothelial cells. Because DNAM-1 is highly expressed on leukocytes, we investigated the role of the DNAM-1–PVR interaction during the monocyte transendothelial migration process. In vitro, both anti–DNAM-1 and anti-PVR mAbs strongly blocked the transmigration of monocytes through the endothelium. Moreover, after anti–DNAM-1 or anti-PVR mAb treatment, monocytes were arrested at the apical surface of the endothelium over intercellular junctions, which strongly suggests that the DNAM-1–PVR interaction occurs during the diapedesis step. Altogether, our results demonstrate that DNAM-1 regulates monocyte extravasation via its interaction with PVR expressed at endothelial junctions on normal cells