Differences in Treatment Response in Bronchial Epithelial Cells from Idiopathic Pulmonary Fibrosis (IPF) Patients: A First Step towards Personalized Medicine?

Idiopathic pulmonary fibrosis (IPF) has a detrimental prognosis despite antifibrotic therapies to which individual responses vary. IPF pathology is associated with oxidative stress, inflammation and increased activation of SRC family kinases (SFK). This pilot study evaluates individual responses to pirfenidone, nintedanib and SFK inhibitor saracatinib, markers of redox homeostasis, fibrosis and inflammation, in IPF-derived human bronchial epithelial (HBE) cells. Differentiated HBE cells from patients with and without IPF were analyzed for potential alterations in redox and profibrotic genes and pro-inflammatory cytokine secretion. Additionally, the effects of pirfenidone, nintedanib and saracatinib on these markers were determined. HBE cells were differentiated into a bronchial epithelium containing ciliated epithelial, basal, goblet and club cells. NOX4 expression was increased in IPF-derived HBE cells but differed on an individual level. In patients with higher NOX4 expression, pirfenidone induced antioxidant gene expression. All drugs significantly decreased NOX4 expression. IL-6 (p = 0.09) and IL-8 secretion (p = 0.014) were increased in IPF-derived HBE cells and significantly reduced by saracatinib. Finally, saracatinib significantly decreased TGF-ß gene expression. Our results indicate that treatment responsiveness varies between IPF patients in relation to their oxidative and inflammatory status. Interestingly, saracatinib tends to be more effective in IPF than standard antifibrotic drugs.

Mindfulness-based stress reduction alters brain activity for breast cancer survivors with chronic neuropathic pain: preliminary evidence from resting-state fMRI.

PURPOSE: Breast cancer continues to be the most commonly diagnosed cancer among Canadian women, with as many as 25-60% of women suffering from chronic neuropathic pain (CNP) as a pervasive consequence of treatment. While pharmacological interventions have shown limited efficacy for the management of CNP to date, psychological interventions, such as mindfulness-based stress reduction (MBSR), may be a promising alterative for improving pain-related problems. The purpose of this study was to use brain imaging methods to investigate this potential. METHODS: Resting-state fMRI was used in female breast cancer survivors with CNP before and after an 8-week MBSR course (n = 13) and compared with a waitlist control group (n = 10). RESULTS: Focusing on the default mode network, the most significant results show greater posterior cingulate connectivity with medial prefrontal regions post-MBSR intervention. Moreover, this change in connectivity correlated with reduced pain severity for the MBSR group. CONCLUSIONS: These results provide empirical evidence of a change in the brain following MBSR intervention associated with changes in the subjective experience of pain. IMPLICATIONS FOR CANCER SURVIVORS: This study gives hope for a non-invasive method of easing the struggle of CNP in women following breast cancer treatment.

Risk stratification of EGFR+ lung cancer diagnosed with panel-based next-generation sequencing.

OBJECTIVE: Panel-based next-generation sequencing (NGS) is increasingly used for the diagnosis of EGFR-mutated non-small-cell lung cancer (NSCLC) and could improve risk assessment in combination with clinical parameters. MATERIALS AND METHODS: To this end, we retrospectively analyzed the outcome of 400 tyrosine kinase inhibitor (TKI)-treated EGFR+ NSCLC patients with validation of results in an independent cohort (n = 130). RESULTS: EGFR alterations other than exon 19 deletions (non-del19), TP53 co-mutations, and brain metastases at baseline showed independent associations of similar strengths with progression-free (PFS hazard ratios [HR] 2.1-2.3) and overall survival (OS HR 1.7-2.2), in combination defining patient subgroups with distinct outcome (EGFR+NSCLC risk Score, "ENS", p < 0.001). Co-mutations beyond TP53 were rarely detected by our multigene panel (<5%) and not associated with clinical endpoints. Smoking did not affect outcome independently, but was associated with non-del19 EGFR mutations (p < 0.05) and comorbidities (p < 0.001). Laboratory parameters, like the blood lymphocyte-to-neutrophil ratio and serum LDH, correlated with the metastatic pattern (p < 0.01), but had no independent prognostic value. Reduced ECOG performance status (PS) was associated with comorbidities (p < 0.05) and shorter OS (p < 0.05), but preserved TKI efficacy. Non-adenocarcinoma histology was also associated with shorter OS (p < 0.05), but rare (2-3 %). The ECOG PS and non-adenocarcinoma histology could not be validated in our independent cohort, and did not increase the range of prognostication alongside the ENS. CONCLUSIONS: EGFR variant, TP53 status and brain metastases predict TKI efficacy and survival in EGFR+ NSCLC irrespective of other currently available parameters ("ENS"). Together, they constitute a practical and reproducible approach for risk stratification of newly diagnosed metastatic EGFR+ NSCLC.

RAS Mutation Decreases Overall Survival After Optimal Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy of Colorectal Peritoneal Metastasis: A Modification Proposal of the Peritoneal Surface Disease Severity Score.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are currently the most accepted treatment for peritoneal metastases from colorectal cancer. Restrictive selection criteria are essential to obtain the best survival benefits for this complex procedure. The most widespread score for patient selection, the peritoneal surface disease severity score (PSDSS), does not include current biological factors that are known to influence on prognosis. We investigated the impact of including RAS mutational status in the selection criteria for these patients. METHODS: We studied the risk factors for survival by multivariate analysis using a prospective database of consecutive patients with carcinomatosis from colorectal origin treated by CRS and HIPEC in our unit from 2009 to 2017. The risk factors obtained were validated in a multicentre, international cohort, including a total of 520 patients from 15 different reference units. RESULTS: A total of 77 patients were selected for local análisis. Only RAS mutational status (HR: 2.024; p = 0.045) and PSDSS stage (HR: 2.90; p = 0.009) were shown to be independent factors for overall survival. Early PSDSS stages I and II associated to RAS mutations impaired their overall survival with no significant differences with PSDSS stage III overall survival (p > 0.05). These results were supported by the international multicentre validation. CONCLUSIONS: By including RAS mutational status, we propose an updated RAS-PSDSS score that outperforms PSDSS alone providing a quick and feasible preoperative assessment of the expected overall survival for patients with carcinomatosis from colorectal origin undergone to CRS + HIPEC.

Expression ratio of the TGFß-inducible gene MYO10 is prognostic for overall survival of squamous cell lung cancer patients and predicts chemotherapy response.

In lung cancer a deregulation of Transforming Growth Factor-ß (TGFß) signaling has been observed. Yet, the impact of TGFß in squamous cell carcinoma of the lung (LUSC) remained to be determined. We combined phenotypic and transcriptome-wide studies and showed that the stimulation of the LUSC cell line SK-MES1 with TGFß results in an increase of migratory invasive properties. The analysis of the dynamics of gene expression by next-generation sequencing revealed that TGFß stimulation orchestrates the upregulation of numerous motility- and actin cytoskeleton-related genes. Among these the non-muscle myosin 10 (MYO10) showed the highest upregulation in a LUSC patient cohort of the Cancer Genome Atlas (TCGA). Knockdown of MYO10 abrogated TGFß-induced collagen gel invasion of SK-MES1 cells. The analysis of MYO10 mRNA expression in paired tissues of 151 LUSC patients with corresponding 80-month clinical follow-up data showed that the mRNA expression ratio of MYO10 in tumor and tumor-free tissue is prognostic for overall survival of LUSC patients and predictive for the response of these patients to adjuvant chemotherapy. Thus, MYO10 represents a new clinical biomarker for this aggressive disease and due to its role in cellular motility and invasion could serve as a potential molecular target for therapeutic interventions in patients with LUSC.

Crystallographic structure and energetics of the Rh(1 0 0)-(3 × 1)-2O phase.

In this study we investigate the crystallographic structure of the Rh(1 0 0)-([Formula: see text])-2O phase by quantitative low energy electron diffraction (LEED) and scanning tunnelling microscopy as well as the energetics of the system applying density functional theory calculations (DFT). The ([Formula: see text]) structure forms upon exposing the clean Rh(1 0 0) surface to 1200 L of oxygen at 520 K. A full-dynamical LEED intensity analysis (Pendry R-factor [Formula: see text]) reveals an oxygen-induced shifted row-reconstruction of the rhodium top layer where every third Rh-row is displaced by half a surface lattice parameter along the [0 1 1]-direction. There are two oxygen atoms within the unit cell which assume threefold coordinated sites on both sides of the shifted Rh-row with one bond to the shifted and two bonds to the unshifted rows. DFT calculations yield a total energy gain of 0.27 eV per oxygen atom compared to adsorption on the unreconstructed surface. This by far overcompensates the energetic penalty of 0.10 eV per oxygen atom for shifting the Rh-row and thus drives the substrate reconstruction. A coadsorption of oxygen at remaining regular sites of the substrate is not observed in experiment and is found to be energetically unfavorable.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in elderly patients. A systematic literature review.

The objective of this review was to evaluate morbidity, mortality and survival outcomes of elderly patients with peritoneal carcinomatosis. A systematic literature search and standardized data collection of primary research publications until June 2016 on morbidity, mortality and survival outcomes in adults aged 65 and older with peritoneal carcinomatosis treated with cytoreduction and HIPEC was performed, using PubMed, EMBASE, Scopus, ClinicalTrials.gov and Cochrane. Bibliographies of relevant reports were also hand-searched to identify all potentially eligible studies. Nine studies were included. Severe morbidity of all elderly patients ranges from 17% to 56% in centers with high experience. In-hospital and 30-day mortality ranges from 0% to 8%. In only two studies were the differences in morbidity and mortality statistically significant related to the control group. However, older adults undergoing cytoreductive surgery and HIPEC consistently had lower survival rates across all study settings and procedure types than younger individuals. In studies that stratified for elderly patients, PCI, completeness of cytoreduction, tumor histology and albumin levels were predictive factors of survival. None of these studies examined quality of life, which precludes including functional outcomes in this review. Differences in exposures, outcomes, and data presented in the studies did not allow for quantification of association using a meta analysis.

Thermal evolution of cobalt deposits on Co3O4(111): atomically dispersed cobalt, two-dimensional CoO islands, and metallic Co nanoparticles.

Cobalt oxide nanomaterials show high activity in several catalytic reactions thereby offering the potential to replace noble metals in some applications. We have developed a well-defined model system for partially reduced cobalt oxide materials aiming at a molecular level understanding of cobalt-oxide-based catalysis. Starting from a well-ordered Co3O4(111) film on Ir(100), we modified the surface by deposition of metallic cobalt. Growth, structure, and adsorption properties of the cobalt-modified surface were investigated by scanning tunneling microscopy (STM), low-energy electron diffraction (LEED), and infrared reflection absorption spectroscopy (IRAS) using CO as a probe molecule. The deposition of a submonolayer of cobalt at 300 K leads to the formation of atomically dispersed cobalt ions distorting the surface layer of the Co3O4 film. Upon annealing to 500 K the Co ions are incorporated into the surface layer forming ordered two-dimensional CoO islands on the Co3O4 grains. At 700 K, Co ions diffuse from the CoO islands into the bulk and the ordered Co3O4(111) surface is restored. Deposition of larger amounts of Co at 300 K leads to formation of metallic Co aggregates on the dispersed cobalt phase. The metallic particles sinter at 500 K and diffuse into the bulk at 700 K. Depending on the degree of bulk reduction, extended Co3O4 grains switch to the CoO(111) structure. All above structures show characteristic CO adsorption behavior and can therefore be identified by IR spectroscopy of adsorbed CO.

A novel, blocking, Fc-silent anti-CD40 monoclonal antibody prolongs nonhuman primate renal allograft survival in the absence of B cell depletion.

CD40-CD154 pathway blockade prolongs renal allograft survival in nonhuman primates (NHPs). However, antibodies targeting CD154 were associated with an increased incidence of thromboembolic complications. Antibodies targeting CD40 prolong renal allograft survival in NHPs without thromboembolic events but with accompanying B cell depletion, raising the question of the relative contribution of B cell depletion to the efficacy of anti-CD40 blockade. Here, we investigated whether fully silencing Fc effector functions of an anti-CD40 antibody can still promote graft survival. The parent anti-CD40 monoclonal antibody HCD122 prolonged allograft survival in MHC-mismatched cynomolgus monkey renal allograft transplantation (52, 22, and 24 days) with accompanying B cell depletion. Fc-silencing yielded CFZ533, an antibody incapable of B cell depletion but still able to potently inhibit CD40 pathway activation. CFZ533 prolonged allograft survival and function up to a defined protocol endpoint of 98-100 days (100, 100, 100, 98, and 76 days) in the absence of B cell depletion and preservation of good histological graft morphology. CFZ533 was well-tolerated, with no evidence of thromboembolic events or CD40 pathway activation and suppressed a gene signature associated with acute rejection. Thus, use of the Fc-silent anti-CD40 antibody CFZ533 appears to be an attractive approach for preventing solid organ transplant rejection.

Subsurface cation vacancy stabilization of the magnetite (001) surface.

Iron oxides play an increasingly prominent role in heterogeneous catalysis, hydrogen production, spintronics, and drug delivery. The surface or material interface can be performance-limiting in these applications, so it is vital to determine accurate atomic-scale structures for iron oxides and understand why they form. Using a combination of quantitative low-energy electron diffraction, scanning tunneling microscopy, and density functional theory calculations, we show that an ordered array of subsurface iron vacancies and interstitials underlies the well-known (√2 × âˆš2)R45° reconstruction of Fe3O4(001). This hitherto unobserved stabilization mechanism occurs because the iron oxides prefer to redistribute cations in the lattice in response to oxidizing or reducing environments. Many other metal oxides also achieve stoichiometry variation in this way, so such surface structures are likely commonplace.

European survey on efficacy and safety of duty-cycled radiofrequency ablation for atrial fibrillation.

AIMS: Duty-cycled radiofrequency ablation (RFA) has been used for atrial fibrillation (AF) for around 5 years, but large-scale data are scarce. The purpose of this survey was to report the outcome of the technique. METHODS AND RESULTS: A survey was conducted among 20 centres from seven European countries including 2748 patients (2128 with paroxysmal and 620 with persistent AF). In paroxysmal AF an overall success rate of 82% [median 80%, interquartile range (IQR) 74-90%], a first procedure success rate of 72% [median 74% (IQR 59-83%)], and a success of antiarrhythmic medication of 59% [median 60% (IQR 39-72%)] was reported. In persistent AF, success rates were significantly lower with 70% [median 74% (IQR 60-92%)]; P = 0.05) as well as the first procedure success rate of 58% [median 55% (IQR 47-81%)]; P = 0.001). The overall success rate was similar among higher and lower volume centres and were not dependent on the duration of experience with duty-cycled RFA (r = -0.08, P = 0.72). Complications were observed in 108 (3.9%) patients, including 31 (1.1%) with symptomatic transient ischaemic attack or stroke, which had the same incidence in paroxysmal and persistent AF (1.1 vs. 1.1%) and was unrelated to the case load (r = 0.24, P = 0.15), bridging anticoagulation to low molecular heparin, routine administration of heparin over the long sheath, whether a transoesophageal echocardiogram was performed in every patient or not and average procedure times. CONCLUSION: Duty-cycled RFA has a self-reported success and complication rate similar to conventional RFA. After technical modifications a prospective registry with controlled data monitoring should be conducted to assess outcome.

A versatile high resolution scanning tunneling potentiometry implementation.

We have developed a new scanning tunneling potentiometry technique which can-with only minor changes of the electronic setup-be easily added to any standard scanning tunneling microscope (STM). This extension can be combined with common STM techniques such as constant current imaging or scanning tunneling spectroscopy. It is capable of performing measurements of the electrochemical potential with microvolt resolution. Two examples demonstrate the versatile application. First of all, we have determined local variations of the electrochemical potential due to charge transport of biased samples down to angstrom length scales. Second, with tip and sample at different temperatures we investigated the locally varying thermovoltage occurring at the tunneling junction. Aside from its use in determining the chemical identity of substances at the sample surface our method provides a controlled way to eliminate the influence of laterally varying thermovoltages on low-bias constant current topographies.

Background removal in scanning tunneling spectroscopy of single atoms and molecules on metal surfaces.

Scanning tunneling spectroscopy has developed into a powerful spectroscopic technique that has found wide application in the atomic scale characterization of the electronic properties of clean surfaces as well as adsorbates and defects at surfaces. However, it still lacks the standard methods for data treatment and removal of artifacts in spectra as they are, e.g., common in photoemission spectroscopy. The properties of the atomic scale tip apex--the probe of the instrument--tend to introduce spurious background signals into tunneling spectra. We present and discuss two methods which permit to extract tip-independent information from low temperature tunneling spectra acquired on single atoms and molecules on single crystal surfaces by background subtraction. The methods rely on a characterization of the tip on the clean metal surface. The performance of both methods is demonstrated and compared for simulated and experimental tunneling spectra.

Local climate aridity influences the distribution of thelastomatoid nematodes of the Australian giant burrowing cockroach.

In this study, we examined the effects of local climate aridity on the richness and composition of the thelastomatoid (Nematoda: Oxyurida) guild parasitizing the Australian giant burrowing cockroach, Macropanesthia rhinoceros (Blattodea: Geoscapheinae). In total, 9 thelastomatoid species parasitized this cockroach in north-eastern Australia (Queensland). Local observed richness ranged from 3 species (in Cooktown, Magnetic Island, Maiden Springs and Whitsunday Island) to 7 species (in Rochford Scrub). The lowest richness occurred in both relatively wet and dry climates, and the highest richness was in moderate climates. Three species, Cordonicola gibsoni, Leidynemella fusiformis and Travassosinema jaidenae, were found at all 13 collection sites. One species, Geoscaphenema megaovum, was found exclusively in dry to moderate climates. The remaining species, Blattophila sphaerolaima, Coronostoma australiae, Desmicola ornata, Hammerschmidtiella hochi and Jaidenema rhinoceratum, were found in moderate climates only. We hypothesize that the egg is the stage in the thelastomatoid life-cycle most vulnerable to the effects of adverse climate and that the geographical distribution for each species is, in part, bound by environments that are too dry, resulting in egg desiccation, and by environments that are too wet, resulting in decreased oxygen uptake across the egg-shell and in osmotic lysing.

A comprehensive analysis of the biogeography of the thelastomatoid pinworms from Australian burrowing cockroaches (Blaberidae: Geoscapheinae, Panesthiinae): no evidence of coevolution.

We report 21 thelastomatoid species parasitizing 31 described and 5 undescribed geoscapheine and panesthiine cockroaches, representing all but 1 of the known species of these subfamilies in Australia. The nematodes have 3 distinct patterns of host distribution: dominant, moderate and rare. The 4 dominant species, Cordonicola gibsoni, Leidynemella fusiformis, Travassosinema jaidenae and Aoruroides queenslandensis, are highly prevalent, found in nearly all host species examined, and broadly distributed. The 8 moderate species have lower prevalences but are still widely distributed. Many of these species are more common in one host subfamily than the other. The remaining 9 rare species have highly restricted host and geographical distributions. Six of the 21 species are exclusive to geoscapheines, 5 to panesthiines and 10 are shared. These patterns suggest that most of the reported thelastomatoid species are generalists rather than specialists, that host-specificity within this group is low and that co-evolutionary speciation has had little, if any, impact on structuring the thelastomatoid fauna of Australian burrowing cockroaches. In a broader context, this study provides the first comprehensive examination of the role of coevolutionary speciation and host specificity in regulating the distribution of pinworms in arthropods.

Exchange interaction between single magnetic adatoms.

The magnetic coupling between single Co atoms adsorbed on a copper surface is determined by probing the Kondo resonance using low-temperature scanning tunneling spectroscopy. The Kondo resonance, which is due to magnetic correlation effects between the spin of a magnetic adatom and the conduction electrons of the substrate, is modified in a characteristic way by the coupling of the neighboring adatom spins. Increasing the interatomic distance of a Cobalt dimer from 2.56 to 8.1 A we follow the oscillatory transition from ferromagnetic to antiferromagnetic coupling. Adding a third atom to the antiferromagnetically coupled dimer results in the formation of a collective correlated state.

Local pressure-induced metallization of a semiconducting carbon nanotube in a crossed junction.

The electronic and vibrational density of states of a semiconducting carbon nanotube in a crossed junction was investigated by elastic and inelastic scanning tunneling spectroscopy. The strong radial compression of the nanotube at the junction induces local metallization spatially confined to a few nanometers. The local electronic modifications are correlated with the observed changes in the radial breathing and G band phonon modes, which react very sensitively to local mechanical deformation. In addition, the experiments reveal the crucial contribution of the image charges to the contact potential at nanotube-metal interfaces.

Kondo effect of molecular complexes at surfaces: ligand control of the local spin coupling.

The spin state of single magnetic atoms and molecules at surfaces is of fundamental interest and may play an important role in future atomic-scale technologies. We demonstrate the ability to tune the coupling between the spin of individual cobalt adatoms with their surroundings by controlled attachment of molecular ligands. The strength of the coupling is determined via the Kondo resonance by low-temperature scanning tunneling spectroscopy. Spatial Kondo resonance mapping is introduced as a novel imaging tool to localize spin centers in magnetic molecules with atomic precision.