Ordering and Demixing Transitions in Multicomponent Widom-Rowlinson Models

We use Monte Carlo techniques and analytical methods to study the phase diagram of multicomponent Widom-Rowlinson models on a square lattice: there are M species all with the same fugacity z and a nearest neighbor hard core exclusion between unlike particles. Simulations show that for M between two and six there is a direct transition from the gas phase at z < z_d (M) to a demixed phase consisting mostly of one species at z > z_d (M) while for M \geq 7 there is an intermediate ``crystal phase'' for z lying between z_c(M) and z_d(M). In this phase, which is driven by entropy, particles, independent of species, preferentially occupy one of the sublattices, i.e. spatial symmetry but not particle symmetry is broken. The transition at z_d(M) appears to be first order for M \geq 5 putting it in the Potts model universality class. For large M the transition between the crystalline and demixed phase at z_d(M) can be proven to be first order with z_d(M) \sim M-2 + 1/M + ..., while z_c(M) is argued to behave as \mu_{cr}/M, with \mu_{cr} the value of the fugacity at which the one component hard square lattice gas has a transition, and to be always of the Ising type. Explicit calculations for the Bethe lattice with the coordination number q=4 give results similar to those for the square lattice except that the transition at z_d(M) becomes first order at M>2. This happens for all q, consistent with the model being in the Potts universality class.Comment: 26 pages, 15 postscript figure

Resveratrol Targeting of Carcinogen-Induced Brain Endothelial Cell Inflammation Biomarkers MMP-9 and COX-2 is Sirt1-Independent

The occurrence of a functional relationship between the release of metalloproteinases (MMPs) and the expression of cyclooxygenase (COX)-2, two inducible pro-inflammatory biomarkers with important pro-angiogenic effects, has recently been inferred. While brain endothelial cells play an essential role as structural and functional components of the blood-brain barrier (BBB), increased BBB breakdown is thought to be linked to neuroinflammation. Chemopreventive mechanisms targeting both MMPs and COX-2 however remain poorly investigated. In this study, we evaluated the pharmacological targeting of Sirt1 by the diet-derived and antiinflammatory polyphenol resveratrol. Total RNA, cell lysates, and conditioned culture media from human brain microvascular endothelial cells (HBMEC) were analyzed using qRT-PCR, immunoblotting, and zymography respectively. Tissue scan microarray analysis of grade I–IV brain tumours cDNA revealed increased gene expression of Sirt-1 from grade I–III but surprisingly not in grade IV brain tumours. HBMEC were treated with a combination of resveratrol and phorbol 12-myristate 13-acetate (PMA), a carcinogen known to increase MMP-9 and COX-2 through NF-κB. We found that resveratrol efficiently reversed the PMA-induced MMP-9 secretion and COX-2 expression. Gene silencing of Sirt1, a critical modulator of angiogenesis and putative target of resveratrol, did not lead to significant reversal of MMP-9 and COX-2 inhibition. Decreased resveratrol inhibitory potential of carcinogen-induced IκB phosphorylation in siSirt1-transfected HBMEC was however observed. Our results suggest that resveratrol may prevent BBB disruption during neuroinflammation by inhibiting MMP-9 and COX-2 and act as a pharmacological NF-κB signal transduction inhibitor independent of Sirt1

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer: results and open issues

The medical treatment of non-small-cell lung cancer (NSCLC) has progressively changed since the introduction of “targeted therapy”. The development of one of these molecular drug categories, e. g., the epidermal growth factor receptor (EGFR) tyrosine-kinase (TK) selective inhibitors, such as the orally active gefitinib and erlotinib, offers an interesting new opportunity. The clinical response rates obtained with their employment in unselected patient populations only account for approximately 10%. Because of this, over the last two years numerous studies have been performed in order to identify the patient subsets that could better benefit from these agents. Not only patient characteristics and clinical-pathological features, such as never-smoking status, female gender, East Asian origin, adenocarcinoma histology, bronchioloalveolar subtype, but also molecular findings, such as somatic mutations in the EGFR gene, emerge as potentially useful prognostic and predictive factors in advanced NSCLC. Further, specifically designed clinical trials are still needed to completely clarify these and other open issues that are reviewed in this paper, in order to clarify all the interesting findings available in the clinical practice

Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369

On realcompact topological vector spaces

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Partitioning of fluorotelomer alcohols (FTOH) to semipermeable membrane devices (SPMD).

Fluorotelomer alcohols (FTOH) are widely used substances that were detected even in remote regions of the world. For the determination of FTOH in the atmosphere, appropriate sampling techniques are needed. In this study, triolein-filled low-density polyethylene tubes were used as semipermeable membrane devices (SPMD) and tested for their suitability as passive air samplers for FTOH. Partitioning to and from SPMD were investigated for four FTOH of different chain length and concentration levels in laboratory and field experiments. FTOH were extracted by liquid-liquid extraction with acetonitrile:n-hexane 1:1 and determined by gas chromatography (GC)-positive ion chemical ionisation mass spectrometry (MS). FTOH behaved differently depending on applied concentrations. At high FTOH levels, compound passage through the membrane and uptake appeared to be best for 6:2 FTOH, but passage of long-chain FTOH was in the same order of magnitude. At low FTOH concentration levels, mass transfer and uptake was best for short-chain FTOH. Partitioning of 4:2 FTOH to SPMD exceeded partitioning of 10:2 FTOH by nearly two orders of magnitude. FTOH partitioning to SPMD seems to be dependent on the fluorinated chain length and controlled by the SPMD membrane acting as a barrier. Migration of long-chain FTOH through the membrane was hampered, probably due to the oleophobic properties of the fluorinated alkyl chain. Because of the constricted diffusion of FTOH through the SPMD membrane at low FTOH levels, an adequate accumulation in the passive sampler is prevented. Thus, sensitivity of the analytical method in combination with the enrichment of FTOH in SPMD was not sufficient to achieve adequate method detection limit at low FTOH levels. Application of SPMD as passive air samplers for FTOH did not seem to be a suitable method for environmentally relevant FTOH concentrations. As a consequence, we can only recommend the use of SPMD for FTOH of presumably high contamination levels

Dosing strategies of imipenem in neonates based on pharmacometric modelling and simulation.

Imipenem is a broad-spectrum antibacterial agent used in critically ill neonates after failure of first-line treatments. Few studies have described imipenem disposition in this population. The objectives of our study were: (i) to characterize imipenem population pharmacokinetics (PK) in a cohort of neonates; and (ii) to conduct model-based simulations to evaluate the performance of six different dosing regimens aiming at optimizing PK target attainment. A total of 173 plasma samples from 82 neonates were collected over 15 years at the Lausanne University Hospital, Switzerland. The majority of study subjects were preterm neonates with a median gestational age (GA) of 27 weeks (range: 24-41), a postnatal age (PNA) of 21 days (2-153) and a body weight (BW) of 1.16 kg (0.5-4.1). PK data were analysed using non-linear mixed-effect modelling (NONMEM). A one-compartment model best characterized imipenem disposition. Population PK parameters estimates of CL and volume of distribution were 0.21 L/h and 0.73 L, with an interpatient variability (CV%) of 20.1% on CL in a representative neonate (GA 27 weeks, PNA 21 days, BW 1.16 kg, serum creatinine, SCr 46.6 μmol/L). GA and PNA exhibited the greatest impact on PK parameters, followed by SCr. These covariates explained 36% and 15% of interindividual variability in CL, respectively.Simulated regimens using a dose of 20-25 mg/kg every 6-12 h according to postnatal age led to the highest PTA (T&gt;MIC over 100% of time). Dosing adjustment according to BW, GA and PNA optimizes imipenem exposure in neonates

The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity.

BAFF and a proliferation-inducing ligand (APRIL), which control B cell homeostasis, are therapeutic targets in autoimmune diseases. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of the BAFF-APRIL receptor TACI, was applied in clinical trials. However, disease activity in multiple sclerosis unexpectedly increased, whereas in systemic lupus erythematosus, atacicept was beneficial. In this study, we show that an endogenous soluble TACI (sTACI) exists in vivo. TACI proteolysis involved shedding by a disintegrin and metalloproteinase 10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by &gamma;-secretase reducing ligand-independent signaling of the remaining C-terminal fragment. The shed ectodomain assembled ligand independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRIL-mediated B cell survival and NF-&kappa;B activation. We determined sTACI levels in autoimmune diseases with established hyperactivation of the BAFF-APRIL system. sTACI levels were elevated both in the cerebrospinal fluid of the brain-restricted autoimmune disease multiple sclerosis correlating with intrathecal IgG production, as well as in the serum of the systemic autoimmune disease systemic lupus erythematosus correlating with disease activity. Together, we show that TACI is sequentially processed by a disintegrin and metalloproteinase 10 and &gamma;-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. It reflects systemic and compartmentalized B cell accumulation and activation