99 research outputs found
Control of Specific Cell Response with Strongly Correlated Functional Domains Embedded in Supported Membranes
Highly uniform and strongly correlated domains of synthetic, fluorinated lipids were incorporated into solid supported lipid membranes. The systematic characterization of variable fluorinated lipid domains revealed a significant dependence of the equilibrium radius of domains on the length of fluorocarbon chains. This can be quantitatively explained within the theoretical framework of an equivalent dipole model. An analysis of the mono–dispersive domains with narrow size distributions and the precise determination of molecular structure parameters with grazing–incidence X-ray diffraction measurements enabled treatment of the inter–domain correlations as two–dimensional colloidal crystallization and calculation of the potential of mean force. Furthermore, the head groups of fluorinated lipids can be modified with alpha –D–mannose and the specific ligand for an apoptosis receptor (CD95L). Both biofunctional molecules attached to the membranes showed specific interactions with target cells, revealing a significant influence of the lateral confinement of domains on the dynamic spreading of macrophages and cancer cell apoptosis. The obtained results demonstrate that synthetically designed lipid anchors can be used as building blocks to create biofunctional micro-/nano- domains for the quantitative regulation of the static and dynamic behavior of cells
Visualizing Collocations in Religious Online Forums
We present results of a project examining the application of text visualization in the context of religious studies and sociology. Our goal is to analyze and compare the online communication of various religious directions. For this contribution we focus on the visualization of collocations for specific religious and spiritual key concepts. As a corpus, we acquired the content of the three religious subreddits /r/Islam, /r/Christianity and /r/Occult for a one-year time span. The overall corpus consists of 700,000 comments and around 50 million tokens. We explore and visualize collocations for the concepts “life”, “religion” and “love”. We discuss the results and to what extent we were able to gather new insights
Safety and anti-tumor activity of lisavanbulin administered as 48-hour infusion in patients with ovarian cancer or recurrent glioblastoma: a phase 2a study
Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862), a microtubule-destabilizing agent. The goal of this study (NCT02895360) was to characterize the safety, tolerability and antitumor activity of lisavanbulin administered as a 48-hour intravenous (IV) infusion at the recommended Phase 2 dose (RP2D) of 70 mg/m. Results from the Phase 1 dose-escalation portion of the study identifying the RP2D have been previously reported. Here, we present the findings from the Phase 2a portion of this study. Methods. This multi-center, open-label study included patients with ovarian, fallopian-tube, or primary peritoneal cancer that was either platinum-resistant or refractory (11 patients), or with first recurrence of glioblastoma (12 patients). Lisavanbulin was administered as a 48-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle. Results. Lisavanbulin was well tolerated in both patient cohorts. Thirteen patients (56.5%) developed 49 adverse events assessed as related to study treatment. The majority were mild or moderate; four were grade 3/4. Sixteen SAEs were reported in nine patients (39.1%), with none considered related to study treatment. No AEs led to permanent treatment discontinuation. Three patients in the ovarian cancer cohort had stable disease with lesion size reductions after two cycles of treatment; in the glioblastoma cohort, one patient showed partial response with a > 90% glioblastoma area reduction as best response, and one patient had stable disease after eight cycles of treatment. Conclusion. This study demonstrated a favorable safety and tolerability profile of 48-hour continuous IV infusion of lisavanbulin in patients with solid extracranial tumors or glioblastoma
Ce-L3-XAS study of the temperature dependence of the 4f occupancy in the Kondo system Ce2Rh3Al9
We have used temperature dependent x-ray absorption at the Ce-L3 edge to
investigate the recently discovered Kondo compound Ce2Rh3Al9. The systematic
changes of the spectral lineshape with decreasing temperature are analyzed and
found to be related to a change in the occupation number, n_f, as the
system undergoes a transition into a Kondo state. The temperature dependence of
indicates a characteristic temperature of 150K, which is clearly related
with the high temperature anomaly observed in the magnetic susceptibility of
the same system. The further anomaly observed in the resistivity of this system
at low temperature (ca. 20K) has no effect on n_f and is thus not of Kondo
origin.Comment: 7 pages, three figures, submitted to PR
Real-World Experience Treating Pediatric Epilepsy Patients With Cenobamate
IntroductionIn one third of all patients with epilepsy, seizure freedom is not achieved through anti-seizure medication (ASM). These patients have an increased risk of earlier death, poorer cognitive development, and reduced quality of life. Cenobamate (CNB) has recently been approved as a promising novel ASM drug for the treatment of adults with focal-onset epilepsy. However, there is little experience for its application in pediatric patients.MethodsIn a multicenter study we evaluated retrospectively the outcome of 16 pediatric patients treated “off label” with CNB.ResultsIn 16 patients with a mean age of 15.38 years, CNB was started at an age of 15.05 years due to DRE. Prior to initiation of therapy, an average of 10.56 (range 3–20) ASM were prescribed. At initiation, patients were taking 2.63 (range 1–4) ASM. CNB was increased by 0.47 ± 0.27mg/kg/d every 2 weeks with a mean maximum dosage of 3.1 mg/kg/d (range 0.89–7) and total daily dose of 182.81 mg (range 50–400 mg). Seizure freedom was achieved in 31.3% and a significant seizure reduction of >50% in 37.5%. Adverse events occurred in 10 patients with fatigue/somnolence as the most common. CNB is taken with high adherence in all but three patients with a median follow-up of 168.5 daysConclusionCenobamate is an effective ASM for pediatric patients suffering from drug-resistant epilepsy. In addition to excellent seizure reduction or freedom, it is well-tolerated. Cenobamate should be considered as a novel treatment for DRE in pediatric patients
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Ultrabroadband 50-130 THz pulses generated via phase-matcheddifference frequency mixing in LiIO3
We report the generation of ultrabroadband pulses spanningthe 50-130 THz frequency range via phase-matched difference frequencymixing within the broad spectrum of sub-10 fs pulses in LiIO_3. Modelcalculations reproduce the octave-spanning spectra and predict few-cycleTHz pulse durations less than 20~;fs. The applicability of this scheme isdemonstrated with 9-fs pulses from a Ti:sapphire oscillator and with 7-fsamplified pulses from a hollow fiber compressor as pumpsources
Searching for Better Plasmonic Materials
Plasmonics is a research area merging the fields of optics and
nanoelectronics by confining light with relatively large free-space wavelength
to the nanometer scale - thereby enabling a family of novel devices. Current
plasmonic devices at telecommunication and optical frequencies face significant
challenges due to losses encountered in the constituent plasmonic materials.
These large losses seriously limit the practicality of these metals for many
novel applications. This paper provides an overview of alternative plasmonic
materials along with motivation for each material choice and important aspects
of fabrication. A comparative study of various materials including metals,
metal alloys and heavily doped semiconductors is presented. The performance of
each material is evaluated based on quality factors defined for each class of
plasmonic devices. Most importantly, this paper outlines an approach for
realizing optimal plasmonic material properties for specific frequencies and
applications, thereby providing a reference for those searching for better
plasmonic materials.Comment: 27 pages, 6 figures, 2 table
Phase 1/2a trial of intravenous BAL101553, a novel controller of the spindle assembly checkpoint, in advanced solid tumours
Background:
BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents.
Methods:
This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D).
Results:
Seventy-three patients received BAL101553 at doses of 15–80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2–3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population.
Conclusions:
The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent’s vascular-disrupting properties.
Clinical trial registration:
EudraCT: 2010-024237-23
Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice
Objective FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations. Methods We compiled 34 patients with a heterozygous (likely) pathogenic FOXG1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1+/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies. Results Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix. Interpretation Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.Peer reviewe
Multi-minicore Disease
Multi-minicore Disease (MmD) is a recessively inherited neuromuscular disorder characterized by multiple cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown. Marked clinical variability corresponds to genetic heterogeneity: the most instantly recognizable classic phenotype characterized by spinal rigidity, early scoliosis and respiratory impairment is due to recessive mutations in the selenoprotein N (SEPN1) gene, whereas recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features comprising external ophthalmoplegia, distal weakness and wasting or predominant hip girdle involvement resembling central core disease (CCD). In the latter forms, there may also be a histopathologic continuum with CCD due to dominant RYR1 mutations, reflecting the common genetic background. Pathogenetic mechanisms of RYR1-related MmD are currently not well understood, but likely to involve altered excitability and/or changes in calcium homeoestasis; calcium-binding motifs within the selenoprotein N protein also suggest a possible role in calcium handling. The diagnosis of MmD is based on the presence of suggestive clinical features and multiple cores on muscle biopsy; muscle MRI may aid genetic testing as patterns of selective muscle involvement are distinct depending on the genetic background. Mutational analysis of the RYR1 or the SEPN1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to address the risk of marked respiratory impairment in SEPN1-related MmD and the possibility of malignant hyperthermia susceptibility in RYR1-related forms. In the majority of patients, weakness is static or only slowly progressive, with the degree of respiratory impairment being the most important prognostic factor
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