Inflammation is critical to the pathogenesis and progression of cancer, with a high neutrophil-lymphocyte ratio (NLR) associated with poor prognosis. The utility of studying NLR in early clinical ...trials is unknown.
This retrospective study evaluated 1300 patients treated in phase 1 clinical trials between July 2004 and February 2014 at the Royal Marsden Hospital (RMH), UK. Data were collected on patient characteristics and baseline laboratory parameters.
The test cohort recruited 300 patients; 53% were female, 35% ECOG 0 and 64% ECOG 1. RMH score was 0-1 in 66% and 2-3 in 34%. The median NLR was 3.08 (IQR 2.06-4.49). Median OS for the NLR quartiles was 10.5 months for quartile-1, 10.3 months for quartile-2, 7.9 months for quartile-3 and 6.5 months for quartile-4 (P<0.0001). Univariate analysis identified RMH score (HR=0.55, P<0.0001), ECOG (HR=0.62, P=0.002) and neutrophils (HR=0.65, P=0.003) to be associated with OS. In multivariate analysis, adjusting for RMH score, ECOG, neutrophils and tumour type, NLR remained significantly associated with OS (P=0.002), with no association with therapeutic steroid use. These results were validated in a further 1000 cancer patients. In the validation cohort, NLR was able to discriminate for OS (P=0.004), as was the RMH score. This was further improved on in the RMH score+NLR50 and RMH score+Log10NLR models, with an optimal NLR cutoff of 3.0.
NLR is a validated independent prognostic factor for OS in patients treated in phase 1 trials. Combining the NLR with the RMH score improves the discriminating ability for OS.
SIMPLE adjoint message passing Towara, M.; Naumann, U.
Optimization methods & software,
11/2018, Letnik:
33, Številka:
4-6
Journal Article
Recenzirano
In the context of numerical simulation a system of partial differential equations is typically solved by discretizing it into a set of linear equations. The non-linear effects in the solution are ...then approximated by repeatedly discretizing, solving and correcting the equations using some outer iteration scheme. One example for such a scheme is the SIMPLE algorithm. In this paper, we show how we obtained an algorithmic adjoint version of the SIMPLE algorithm in OpenFOAM with particular focus on the adjoint message passing interface communication inside the linear solvers. Due to the sparse matrix storage and specifics of the implementation of the linear solvers, this method requires special attention to the inner workings of said structures and algorithms. We show the feasibility of the chosen method by presenting two case studies. In addition to the SIMPLE algorithm, the presented ideas are applicable to a wide range of algorithms whenever linear systems are embedded into an overlying non-linear context.
The growing recognition of a dichotomous role of astrocytes in neurodegenerative processes has heightened the need for unraveling distinct astrocytic subtypes in neurological disorders. In multiple ...system atrophy (MSA), a rare, rapidly progressing atypical Parkinsonian disease characterized by increased astrocyte reactivity. However the specific contribution of astrocyte subtypes to neuropathology remains elusive. Hence, we first set out to profile glial fibrillary acidic protein levels in astrocytes across the human post mortem motor cortex, putamen, and substantia nigra of MSA patients and observed an overall profound astrocytic response. Matching the post mortem human findings, a similar astrocytic phenotype was present in a transgenic MSA mouse model. Notably, MSA mice exhibited a decreased expression of the glutamate transporter 1 and glutamate aspartate transporter in the basal ganglia, but not the motor cortex. We developed an optimized astrocyte isolation protocol based on magnetic-activated cell sorting via ATPase Na+/K+ transporting subunit beta 2 and profiled the transcriptomic landscape of striatal and cortical astrocytes in transgenic MSA mice. The gene expression profile of astrocytes in the motor cortex displayed an anti-inflammatory signature with increased oligodendroglial and pro-myelinogenic expression pattern. In contrast, striatal astrocytes were defined by elevated pro-inflammatory transcripts accompanied by dysregulated genes involved in homeostatic functions for lipid and calcium metabolism. These findings provide new insights into a region-dependent, dichotomous astrocytic response-potentially beneficial in the cortex and harmful in the striatum-in MSA suggesting a differential role of astrocytes in MSA-related neurodegenerative processes.
Anorexia nervosa (AN) poses a major burden on families. Carers (e.g. parents or partners) of people with AN are often highly distressed and may inadvertently respond in ways that can contribute to ...the maintenance of the disorder, e.g. through high levels of over-involvement and criticism also known as expressed emotion (EE). This study aimed to evaluate the efficacy of a novel web-based systemic cognitive-behavioural (CBT) intervention for carers of people with AN, designed to reduce carer distress and teach skills in how to offer effective support.
Carers of people with AN (n=64) were randomly allocated to either the web-intervention, overcoming anorexia online, with limited clinician supportive guidance (by email or phone), or to ad-hoc usual support from the UK patient and carer organization Beat. Carer outcomes were assessed at post-treatment (4 months) and follow-up (6 months).
Compared with the control intervention, web-based treatment significantly reduced carers' anxiety and depression (primary outcome) at post-treatment, with a similar trend in carers' EE. Other secondary outcomes did not favour the online intervention. Gains were maintained at follow-up.
This is the first ever study to use an online CBT program to successfully reduce carer distress and improve carers' ability to support the person with AN.
Abstract
The
KArlsruhe TRItium Neutrino
(KATRIN) experiment
aims to measure the neutrino mass with a sensitivity of 0.2 eV
(90 % CL). This will be achieved by a precision measurement of the
endpoint ...region of the β-electron spectrum of tritium
decay. The β-electrons are produced in the
Windowless
Gaseous Tritium Source
(WGTS) and guided magnetically through the
beamline. In order to accurately extract the neutrino mass the
source activity is required to be stable and known to a high
precision. The WGTS therefore undergoes constant extensive
monitoring from several measurement systems. The
Forward Beam
Monitor
(FBM) is one such monitoring system.
The FBM system comprises a complex mechanical setup capable of
inserting a detector board into the KATRIN beamline with a
positioning precision of better than 0.3 mm. The electron flux
density at that position is on the order of
10
6
s
-1
mm
-2
. The detector board contains two silicon
detector chips of
p-i-n
diode type which can measure the
β-electron flux from the source with a precision of 0.1 %
within 60 s with an energy resolution of FWHM = 2 keV.
The unique challenge in developing the FBM arises from its
designated operating environment inside the Cryogenic Pumping
Section which is a potentially tritium contaminated ultra-high
vacuum chamber at cryogenic temperatures in the presence of a 1 T
strong magnetic field. Each of these parameters do strongly limit
the choice of possible materials which e.g. caused difficulties in
detector noise reduction, heat dissipation and lubrication. In order
to completely remove the FBM from the beam tube a 2 m long
traveling distance into the beamline is needed demanding a robust as
well as highly precise moving mechanism.
Only limited efficacy and tolerability data on raltegravir (RAL) use are currently available. Study objectives were to describe the efficacy and tolerability profile of RAL-based antiretroviral ...therapy (ART) in routine clinical practice in Germany. The WIP study (WIP = “Wirksamkeit von Isentress unter Praxisbedingungen”, Efficacy of Isentress under routine clinical conditions) was a prospective, multi-centre cohort study in Germany. Human immunodeficiency virus (HIV)-infected patients aged ≥ 18 years in whom combinational ART with RAL 400 mg BID was indicated were enrolled. The primary endpoint was virologic response (HIV-RNA <50 copies/mL; non-completion equals failure) after 48 weeks. Of 451 patients, 85.1% (n = 384) were still receiving RAL at week 48. At baseline (BL), the prevalence of concomitant diseases was higher in patients of the age group ≥50 years (94.2% vs. 75.7%) as well as concomitant medications (74.8 % vs. 55.4%). Virologic response at week 48 was 74.7% (overall), 75.0% (naïve at BL), 81.5% (suppressed at BL), 47.1% (interrupted previous treatment at BL) and 64.9% (failing at BL), without significant differences by age group. A significant correlation of achievement of HIV-RNA <50 copies/mL was seen with treatment status at BL (p = 0.004). In addition, 77.3 % of the patients with a CD4 cell count >200 cells/µL at BL achieved HIV-RNA <50 copies/mL (p = 0.029). RAL was well tolerated with 80 adverse events (AEs) in 49 patients (10.9%) and 8 serious AEs (SAEs) in 6 patients (1.3%) reported to be drug related. A total of 22 patients (4.9%) discontinued treatment due to AEs. The WIP study shows that the previously reported efficacy and safety profile of RAL can be achieved in a population with multiple comorbidities and comedications, with no major difference observed in ageing patients (≥50 years) vs. younger patients. RAL is therefore an attractive treatment option in routine medical care in Germany.
The KArlsruhe TRItium Neutrino (KATRIN) experiment will measure the mass of the neutrino with a sensitivity of 0.2 eV (90 % CL). The Forward Beam Monitor (FBM) is a monitoring system which comprises ...of a complex mechanical setup capable of inserting a detector board into the KATRIN beamline at the end of the source and transport section. The detector board contains a Hall sensor, a temperature gauge, and two PIN diodes which can detect electrons from the source with a precision of 0.1 % in less than a minute within an electron flux density of 106 s−1mm−2.
CP-31398 is a prototype small molecule that stabilizes the active conformation of p53 and promotes p53 activity in cancer cell lines with mutant or wild-type p53. Here, we report that CP-31398 ...induces p53 reporter gene activity and p21 expression in all of 11 glioma cell lines harboring wild-type or mutant p53, but not in p53-null LN-308 cells. Upon prolonged exposure to CP-31398, all glioma cell lines undergo caspase-independent and bcl-x(L)-insensitive cell death with EC(50) concentrations of 10-36 microM. By comparing p53 wild-type U87MG and p53-null LN-308 cells expressing the temperature-sensitive p53(V135A) mutant, we delineate two pathways of CP-31398-induced cell death: an early, p53-dependent pathway that requires (new p53) protein synthesis and a late, p53-independent pathway characterized by aurintricarboxylic acid -sensitive calcium release and epiphenomenal free radical formation. Post-transcriptional repression of p53 synthesis by an intracellularly transcribed short interfering RNA confirmed the presence of these two pathways of cell death. These observations point out some of the liabilities of CP-31398 as a prototype p53-based therapeutic and define a rationale for further refinement of small molecules that specifically target the p53 pathway, but lack the p53-independent effects.
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