Endarterectomy of the Aneurysm Sac in Open Abdominal Aortic Aneurysm Repair Reduces Perigraft Seroma and Improves Graft Incorporation

Background: Fluid around the graft in the original aneurysm sac after open abdominal aortic aneurysm (AAA) repair is a poorly researched phenomenon. If large, such perigraft seroma can cause symptoms of compression, and cases of rupture have even been described. We assessed whether endarterectomy of the aneurysm sac reduces the incidence of perigraft fluid and improves graft incorporation. Design and methods: Starting in July 2005, all patients with elective open AAA repair were alternately treated either with conventional thrombectomy or thrombectomy plus endarterectomy of the aneurysm sac. All patients were treated with a polytetrafluoroethylene (PTFE) graft. The maximum axial width of the perigraft fluid collection was measured on computed tomography (CT) scans 1year after operation. Results: The CT scans of 115 patients were available; 56 had endarterectomy of the aneurysm sac and 59 did not. Fluid collections were significantly smaller in patients with endarterectomy (median width 4.0 versus 8.0mm; P=0.0001). Eight patients with endarterectomy had a fluid collection wider than 10mm compared to 28 patients without endarterectomy (OR 0.18, 95% CI 0.07-0.46). After endarterectomy, 17 patients had radiological signs of complete graft incorporation in comparison to only 6 patients without endarterectomy (OR 3.85, 95% CI 1.39-10.66). No patients were symptomatic or reoperated for perigraft seroma. Conclusions: Endarterectomy of the aneurysm sac in open AAA repair appears to improve graft incorporation. The high rate of asymptomatic perigraft seroma is surprising, and its clinical significance is unknown. Ultrafiltration of PTFE grafts may be an underlying mechanis

Active multi-point microrheology of cytoskeletal networks

Active microrheology is a valuable tool to determine viscoelastic properties of polymer networks. Observing the response of the beads to the excitation of a reference leads to dynamic and morphological information of the material. In this work we present an expansion of the well-known active two-point microrheology. By measuring the response of multiple particles in a viscoelastic medium in response to the excitation of a reference particle, we are able to determine the force propagation in the polymer network. For this purpose a lock-in technique is established that allows for extraction of the periodical motion of embedded beads. To exert a sinusoidal motion onto the reference bead an optical tweezers setup in combination with a microscope is used to investigate the motion of the response beads. From the lock-in data the so called transfer tensor can be calculated, which is a direct measure for the ability of the network to transmit mechanical forces. We also take a closer look at the influence of noise on lock-in measurements and state some simple rules for improving the signal-to-noise ratio

Sponge-Like Behaviour in Isoreticular Cu(Gly-His-X) Peptide-Based Porous Materials

We report two isoreticular 3D peptide-based porous frameworks formed by coordination of the tripeptides Gly-l-His-Gly and Gly-l-His-l-Lys to Cu(II) which display sponge-like behaviour. These porous materials undergo structural collapse upon evacuation that can be reversed by exposure to water vapour, which permits recovery of the original open channel structure. This is further confirmed by sorption studies that reveal that both solids exhibit selective sorption of H(2)O while CO(2) adsorption does not result in recovery of the original structures. We also show how the pendant aliphatic amine chains, present in the framework from the introduction of the lysine amino acid in the peptidic backbone, can be post-synthetically modified to produce urea-functionalised networks by following methodologies typically used for metal–organic frameworks built from more rigid “classical” linkers

Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with limited treatment options. One of the standard treatments for MPM is chemotherapy, which consists of concurrent treatment with pemetrexed and cisplatin. Pemetrexed limits tumor growth by inhibiting critical metabolic enzymes involved in nucleotide synthesis. Cisplatin causes direct DNA damage, such as intra-strand and inter-strand cross-links, which are repaired by the nucleotide excision repair pathway, which depends on relatively high nucleotide levels. We hypothesized that prolonged pretreatment with pemetrexed might deplete nucleotide pools, thereby sensitizing cancer cells to subsequent cisplatin treatment. The MPM cell lines ACC-MESO-1 and NCI-H28 were treated for 72 h with pemetrexed. Three treatment schedules were evaluated by initiating 24 h of cisplatin treatment at 0 h (concomitant), 24 h, and 48 h relative to pemetrexed treatment, resulting in either concomitant administration or pemetrexed pretreatment for 24 h or 48 h, respectively. Multicolor flow cytometry was performed to detect γH2AX (phosphorylation of histone H2AX), a surrogate marker for the activation of the DNA damage response pathway. DAPI staining of DNA was used to analyze cell cycle distribution. Forward and side scatter intensity was used to distinguish subpopulations based on cellular size and granularity, respectively. Our study revealed that prolonged pemetrexed pretreatment for 48 h prior to cisplatin significantly reduced long-term cell growth. Specifically, pretreatment for 48 h with pemetrexed induced a cell cycle arrest, mainly in the G2/M phase, accumulation of persistent DNA damage, and induction of a senescence phenotype. The present study demonstrates that optimizing the treatment schedule by pretreatment with pemetrexed increases the efficacy of the pemetrexed-cisplatin combination therapy in MPM. We show that the observed benefits are associated with the persistence of treatment-induced DNA damage. Our study suggests that an adjustment of the treatment schedule could improve the efficacy of the standard chemotherapy regimen for MPM and might improve patient outcomes

Design and methodology of the Swiss Transplant Cohort Study (STCS): a comprehensive prospective nationwide long-term follow-up cohort

In Switzerland, organ procurement is well organized at the national-level but transplant outcomes have not been systematically monitored so far. Therefore, a novel project, the Swiss Transplant Cohort Study (STCS), was established. The STCS is a prospective multicentre study, designed as a dynamic cohort, which enrolls all solid organ recipients at the national level. The features of the STCS are a flexible patient-case system that allows capturing all transplant scenarios and collection of patient-specific and allograft-specific data. Beyond comprehensive clinical data, specific focus is directed at psychosocial and behavioral factors, infectious disease development, and bio-banking. Between May 2008 and end of 2011, the six Swiss transplant centers recruited 1,677 patients involving 1,721 transplantations, and a total of 1,800 organs implanted in 15 different transplantation scenarios. 10% of all patients underwent re-transplantation and 3% had a second transplantation, either in the past or during follow-up. 34% of all kidney allografts originated from living donation. Until the end of 2011 we observed 4,385 infection episodes in our patient population. The STCS showed operative capabilities to collect high-quality data and to adequately reflect the complexity of the post-transplantation process. The STCS represents a promising novel project for comparative effectiveness research in transplantation medicin

Better survival in right-sided versus left-sided stage I - III colon cancer patients

Background: The distinction between right-sided and left-sided colon cancer has recently received considerable attention due to differences regarding underlying genetic mutations. There is an ongoing debate if right- versus left-sided tumor location itself represents an independent prognostic factor. We aimed to investigate this question by using propensity score matching. Methods: Patients with resected, stage I - III colon cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) database (2004–2012). Both univariable and multivariable Cox regression as well as propensity score matching were used. Results: Overall, 91,416 patients (51,937 [56.8%] with right-sided, 39,479 [43.2%] with left-sided colon cancer; median follow-up 38 months) were eligible. In univariable analysis, patients with right-sided cancer had worse overall (hazard ratio [HR] = 1.32, 95% CI:1.29–1.36, P < 0.001) and cancer-specific survival (HR = 1.26, 95% CI:1.21–1.30, P < 0.001) compared to patients with left-sided cancer. After propensity score matching, the prognosis of right-sided carcinomas was better regarding overall (HR = 0.92, 95% CI: 0.89 − 0.94, P < 0.001) and cancer-specific survival (HR = 0.90, 95% CI:0.87 − 0.93, P < 0.001). In stage I and II, the prognosis of right-sided cancer was better for overall (HR = 0.89, 95% CI:0.84–0.94 and HR = 0.85, 95% CI:0.81–0.89) and cancer-specific survival (HR = 0.71, 95% CI:0.64 − 0.79 and HR = 0.75, 95% CI:0.70–0.80). Right- and left-sided colon cancer had a similar prognosis for stage III (overall: HR = 0.99, 95% CI:0.95–1.03 and cancer-specific: HR = 1.04, 95% CI:0.99–1.09). Conclusions: This population-based analysis on stage I - III colon cancer provides evidence that the prognosis of localized right-sided colon cancer is better compared to left-sided colon cancer. This questions the paradigm from previous research claiming a worse survival in right-sided colon cancer patients

An optimized protocol for the generation and monitoring of conditional orthotopic lung cancer in the KP mouse model using an adeno-associated virus vector compatible with biosafety level 1.

BACKGROUND The inducible Kras/p53 lung adenocarcinoma mouse model, which faithfully recapitulates human disease, is routinely initiated by the intratracheal instillation of a virus-based Cre recombinase delivery system. Handling virus-based delivery systems requires elevated biosafety levels, e.g., biosafety level 2 (BSL-2). However, in experimental animal research facilities, following exposure to viral vectors in a BSL-2 environment, rodents may not be reclassified to BSL-1 according to standard practice, preventing access to small animal micro-computed tomography (micro-CT) scanners that are typically housed in general access areas such as BSL-1 rooms. Therefore, our goal was to adapt the protocol so that the Cre-induced KP mouse model could be handled under BSL-1 conditions during the entire procedure. RESULTS The Kras-Lox-STOP-Lox-G12D/p53 flox/flox (KP)-based lung adenocarcinoma mouse model was activated by intratracheal instillation of either an adenoviral-based or a gutless, adeno-associated viral-based Cre delivery system. Tumor growth was monitored over time by micro-CT. We have successfully substituted the virus-based Cre delivery system with a commercially available, gutless, adeno-associated, Cre-expressing vector that allows the KP mouse model to be handled and imaged in a BSL-1 facility. By optimizing the anesthesia protocol and switching to a microscope-guided vector instillation procedure, productivity was increased and procedure-related complications were significantly reduced. In addition, repeated micro-CT analysis of individual animals allowed us to monitor tumor growth longitudinally, dramatically reducing the number of animals required per experiment. Finally, we documented the evolution of tumor volume for different doses, which revealed that individual tumor nodules induced by low-titer AAV-Cre transductions can be monitored over time by micro-CT. CONCLUSION Modifications to the anesthesia and instillation protocols increased the productivity of the original KP protocol. In addition, the switch to a gutless, adeno-associated, Cre-expressing vector allowed longitudinal monitoring of tumor growth under BSL-1 conditions, significantly reducing the number of animals required for an experiment, in line with the 3R principles

A New Immortalized Human Alveolar Epithelial Cell Model to Study Lung Injury and Toxicity on a Breathing Lung-On-Chip System

The evaluation of inhalation toxicity, drug safety and efficacy assessment, as well as the investigation of complex disease pathomechanisms, are increasingly relying on in vitro lung models. This is due to the progressive shift towards human-based systems for more predictive and translational research. While several cellular models are currently available for the upper airways, modelling the distal alveolar region poses several constraints that make the standardization of reliable alveolar in vitro models relatively difficult. In this work, we present a new and reproducible alveolar in vitro model, that combines a human derived immortalized alveolar epithelial cell line ((AX)iAEC) and organ-on-chip technology mimicking the lung alveolar biophysical environment ((AX)lung-on-chip). The latter mimics key features of the in vivo alveolar milieu: breathing-like 3D cyclic stretch (10% linear strain, 0.2 Hz frequency) and an ultrathin, porous and elastic membrane. (AX)iAECs cultured on-chip were characterized for their alveolar epithelial cell markers by gene and protein expression. Cell barrier properties were examined by TER (Transbarrier Electrical Resistance) measurement and tight junction formation. To establish a physiological model for the distal lung, (AX)iAECs were cultured for long-term at air-liquid interface (ALI) on-chip. To this end, different stages of alveolar damage including inflammation (via exposure to bacterial lipopolysaccharide) and the response to a profibrotic mediator (via exposure to Transforming growth factor β1) were analyzed. In addition, the expression of relevant host cell factors involved in SARS-CoV-2 infection was investigated to evaluate its potential application for COVID-19 studies. This study shows that (AX)iAECs cultured on the (AX)lung-on-chip exhibit an enhanced in vivo-like alveolar character which is reflected into: 1) Alveolar type 1 (AT1) and 2 (AT2) cell specific phenotypes, 2) tight barrier formation (with TER above 1,000 Ω cm(2)) and 3) reproducible long-term preservation of alveolar characteristics in nearly physiological conditions (co-culture, breathing, ALI). To the best of our knowledge, this is the first time that a primary derived alveolar epithelial cell line on-chip representing both AT1 and AT2 characteristics is reported. This distal lung model thereby represents a valuable in vitro tool to study inhalation toxicity, test safety and efficacy of drug compounds and characterization of xenobiotics