Fluid-solid transitions in photonic crystals of soft, thermoresponsive microgels.

Microgels are often discussed as well-suited model system for soft colloids. In contrast to rigid spheres, the microgel volume and, coupled to this, the volume fraction in dispersion can be manipulated by external stimuli. This behavior is particularly interesting at high packings where phase transitions can be induced by external triggers such as temperature in the case of thermoresponsive microgels. A challenge, however, is the determination of the real volume occupied by these deformable, soft objects and consequently, to determine the boundaries of the phase transitions. Here we propose core-shell microgels with a rigid silica core and a crosslinked, thermoresponsive poly-N-isopropylacrylamide (PNIPAM) shell with a carefully chosen shell-to-core size ratio as ideal model colloids to study fluid-solid transitions that are inducible by millikelvin changes in temperature. Specifically, we identify the temperature ranges where crystallization and melting occur using absorbance spectroscopy in a range of concentrations. Slow annealing from the fluid to the crystalline state leads to photonic crystals with Bragg peaks in the visible wavelength range and very narrow linewidths. Small-angle X-ray scattering is then used to confirm the structure of the fluid phase as well as the long-range order, crystal structure and microgel volume fraction in the solid phase. Thanks to the scattering contrasts and volume ratio of the cores with respect to the shells, the scattering data do allow for form factor analysis revealing osmotic deswelling at volume fractions approaching and also exceeding the hard sphere packing limit.

Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA).

BACKGROUND: Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future. DESIGN: The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field. RESULTS: Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues. CONCLUSIONS: We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic.

A photogrammetric method for target monitoring inside the MEG II detector.

An automatic target monitoring method based on photographs taken by a CMOS photo-camera has been developed for the MEG II detector. The technique could be adapted for other fixed-target experiments requiring good knowledge of their target position to avoid biases and systematic errors in measuring the trajectories of the outcoming particles. A CMOS-based, high resolution, high radiation tolerant, and high magnetic field resistant photo-camera was mounted inside the MEG II detector at the Paul Scherrer Institute (Switzerland). MEG II is used to search for lepton flavor violation in muon decays. The photogrammetric method's challenges, affecting measurements of low momentum particles' tracks, are the high magnetic field of the spectrometer, high radiation levels, tight space constraints, and the need to limit the material budget in the tracking volume. The camera is focused on the dot pattern drawn on the thin MEG II target, about 1 m away from the detector endcaps where the photo-camera is placed. Target movements and deformations are monitored by comparing images of the dots taken at various times during the measurement. The images are acquired with a Raspberry board and analyzed using custom software. Global alignment to the spectrometer is guaranteed by corner cubes placed on the target support. As a result, the target monitoring fulfills the needs of the experiment.

Demonstration of Muon-Beam Transverse Phase-Space Compression.

We demonstrate efficient transverse compression of a 12.5 MeV/c muon beam stopped in a helium gas target featuring a vertical density gradient and crossed electric and magnetic fields. The muon stop distribution extending vertically over 14 mm was reduced to a 0.25 mm size (rms) within 3.5 µs. The simulation including cross sections for low-energy µ^{+}-He elastic and charge exchange (µ^{+}↔ muonium) collisions describes the measurements well. By combining the transverse compression stage with a previously demonstrated longitudinal compression stage, we can improve the phase space density of a µ^{+} beam by a factor of 10^{10} with 10^{-3} efficiency.

Exo-Ocean Exploration with Deep-Sea Sensor and Platform Technologies.

One of Saturn's largest moons, Enceladus, possesses a vast extraterrestrial ocean (i.e., exo-ocean) that is increasingly becoming the hotspot of future research initiatives dedicated to the exploration of putative life. Here, a new bio-exploration concept design for Enceladus' exo-ocean is proposed, focusing on the potential presence of organisms across a wide range of sizes (i.e., from uni- to multicellular and animal-like), according to state-of-the-art sensor and robotic platform technologies used in terrestrial deep-sea research. In particular, we focus on combined direct and indirect life-detection capabilities, based on optoacoustic imaging and passive acoustics, as well as molecular approaches. Such biologically oriented sampling can be accompanied by concomitant geochemical and oceanographic measurements to provide data relevant to exo-ocean exploration and understanding. Finally, we describe how this multidisciplinary monitoring approach is currently enabled in terrestrial oceans through cabled (fixed) observatories and their related mobile multiparametric platforms (i.e., Autonomous Underwater and Remotely Operated Vehicles, as well as crawlers, rovers, and biomimetic robots) and how their modified design can be used for exo-ocean exploration.

MicroRNA-related genetic variants in iron regulatory genes, dietary iron intake, microRNAs and lung cancer risk.

Background: Genetic variations in MicroRNA (miRNA) binding sites may alter structural accessibility of miRNA binding sites to modulate risk of cancer. This large-scale integrative multistage study was aimed to evaluate the interplay of genetic variations in miRNA binding sites of iron regulatory pathway, dietary iron intake and lung cancer (LC) risk. Patients and methods: The interplay of genetic variant, dietary iron intake and LC risk was assessed in large-scale case-control study. Functional characterization of the validated SNP and analysis of target miRNAs were performed. Results: We found that the miRNA binding site SNP rs1062980 in 3' UTR of Iron-Responsive Element Binding protein 2 gene (IREB2) was associated with a 14% reduced LC risk (P value = 4.9×10 - 9). Comparing to AA genotype, GG genotype was associated with a 27% reduced LC risk. This association was evident in males and ever-smokers but not in females and never-smokers. Higher level of dietary iron intake was significantly associated with 39% reduced LC risk (P value = 2.0×10 - 8). This association was only present in individuals with AG + AA genotypes with a 46% reduced risk (P value = 1.0×10 - 10), but not in GG genotype. The eQTL-analysis showed that rs1062980 significantly alters IREB2 expression level. Rs1062980 is predicted to alter a miR-29 binding site on IREB2 and indeed the expression of miR-29 is inversely correlated with IREB2 expression. Further, we found that higher circulating miR-29a level was significantly associated with 78% increased LC risk. Conclusion: The miRNA binding site SNP rs1062980 in iron regulatory pathway, which may alter the expression of IREB2 potentially through modulating the binding of miR-29a, together with dietary iron intake may modify risk of LC both individually and jointly. These discoveries reveal novel pathway for understanding lung cancer tumorigenesis and risk stratification.

MicroRNA profiling in clear cell renal cell carcinoma tissues potentially links tumorigenesis and recurrence with obesity.

BACKGROUND: Twenty to 40% localised RCC patients may experience recurrence after curative surgery. Limited miRNA predictors have been identified for ccRCC recurrence. METHODS: Through a multi-phase study design, we analysed miRNAs in tissues obtained from 203 ccRCC patients. Paired t-test was used for tumour-normal comparisons and Cox regression model was performed to compute hazard ratios (HRs) and corresponding 95% CIs. RESULTS: A 17-miRNA signature was identified that can concordantly classify >95% of tumour/adjacent normal samples. Significant enrichment was found as 6 out of 17 miRNAs were associated with obesity (binomial probability=0.001). Decreased levels of miR-204-5p and miR-139-5p were each associated with an approximately three-fold increased risk of recurrence (P<0.01). Risk score was generated based on expressions of miR-204-5p and miR-139-5p, and the trend test was significant in both discovery and validation sets (Pfor trend<0.05). Striking MST reduction was observed for patients with a high-risk score (high vs low: discovery, 9.4 vs >97.7 months; validation, 20.8 vs >70.3 months). Expressions of miR-204-5p were also associated with body mass index (ß=5.64, P<0.001). Significant inverse correlations were observed and validated between miR-204-5p and 13 obesity-related genes (r<0, P<0.01). CONCLUSIONS: We identified 17 miRNAs dysregulated in ccRCC tissues and showed that low expressions of miR-204-5p and miR-139-5p were associated with the higher risk of recurrence. The link between miR-204-5p and ccRCC recurrence may be partially mediated by regulating the expression of targeted obesity-related genes.

International cancer seminars: a focus on kidney cancer.

Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer. To summarize important achievements and identify prominent research questions that remain, a workshop was organized by IARC and the US NCI. A series of 'difficult questions' were formulated, which should be given future priority in the areas of population, genomic and clinical research.

Comparing the biological washout of ß+-activity induced in mice brain after 12C-ion and proton irradiation.

In clinical ion beam therapy, protons as well as heavier ions such as carbon are used for treatment. For protons, ß(+)-emitters are only induced by fragmentation reactions in the target (target fragmentation), whereas for heavy ions, they are additionally induced by fragmentations of the projectile (further referred to as autoactivation). An approach utilizing these processes for treatment verification, by comparing measured Positron Emission Tomography (PET) data to predictions from Monte Carlo simulations, has already been clinically implemented. For an accurate simulation, it is important to consider the biological washout of ß(+)-emitters due to vital functions. To date, mathematical expressions for washout have mainly been determined by using radioactive beams of (10)C- and (11)C-ions, both ß(+)-emitters, to enhance the counting statistics in the irradiated area. Still, the question of how the choice of projectile (autoactivating or non-autoactivating) influences the washout coefficients, has not been addressed. In this context, an experiment was carried out at the Heidelberg Ion Beam Therapy Center with the purpose of directly comparing irradiation-induced biological washout coefficients in mice for protons and (12)C-ions. To this aim, mice were irradiated in the brain region with protons and (12)C-ions and measured after irradiation with a PET/CT scanner (Siemens Biograph mCT). After an appropriate waiting time, the mice were sacrificed, then irradiated and measured again under similar conditions. The resulting data were processed and fitted numerically to deduce the main washout parameters. Despite the very low PET counting statistics, a consistent difference could be identified between (12)C-ion and proton irradiated mice, with the (12)C data being described best by a two component fit with a combined medium and slow washout fraction of 0.50 ± 0.05 and the proton mice data being described best by a one component fit with only one (slow) washout fraction of 0.73 ± 0.06.

Inflammation-related genetic variants predict toxicity following definitive radiotherapy for lung cancer.

Definitive radiotherapy improves locoregional control and survival in inoperable non-small cell lung cancer patients. However, radiation-induced toxicities (pneumonitis/esophagitis) are common dose-limiting inflammatory conditions. We therefore conducted a pathway-based analysis to identify inflammation-related single-nucleotide polymorphisms associated with radiation-induced pneumonitis or esophagitis. A total of 11,930 single-nucleotide polymorphisms were genotyped in 201 stage I-III non-small cell lung cancer patients treated with definitive radiotherapy. Validation was performed in an additional 220 non-small cell lung cancer cases. After validation, 19 single-nucleotide polymorphisms remained significant. A polygenic risk score was generated to summarize the effect from validated single-nucleotide polymorphisms. Significant improvements in discriminative ability were observed when the polygenic risk score was added into the clinical/epidemiological variable-based model. We then used 277 lymphoblastoid cell lines to assess radiation sensitivity and expression quantitative trait loci (eQTL) relationships of the identified single-nucleotide polymorphisms. Three genes (PRKCE, DDX58, and TNFSF7) were associated with radiation sensitivity. We concluded that inflammation-related genetic variants could contribute to the development of radiation-induced toxicities.

Measurement of muon capture on the proton to 1% precision and determination of the pseudoscalar coupling gP.

The MuCap experiment at the Paul Scherrer Institute has measured the rate Λ(S) of muon capture from the singlet state of the muonic hydrogen atom to a precision of 1%. A muon beam was stopped in a time projection chamber filled with 10-bar, ultrapure hydrogen gas. Cylindrical wire chambers and a segmented scintillator barrel detected electrons from muon decay. Λ(S) is determined from the difference between the µ(-) disappearance rate in hydrogen and the free muon decay rate. The result is based on the analysis of 1.2 × 10(10) µ(-) decays, from which we extract the capture rate Λ(S) = (714.9 ± 5.4(stat) ± 5.1(syst)) s(-1) and derive the proton's pseudoscalar coupling g(P)(q(0)(2) = -0.88 m(µ)(2)) = 8.06 ± 0.55.

New constraint on the existence of the µ+ → e+ γ decay.

The analysis of a combined data set, totaling 3.6 × 10(14) stopped muons on target, in the search for the lepton flavor violating decay µ(+) → e(+)γ is presented. The data collected by the MEG experiment at the Paul Scherrer Institut show no excess of events compared to background expectations and yield a new upper limit on the branching ratio of this decay of 5.7 × 10(-13) (90% confidence level). This represents a four times more stringent limit than the previous world best limit set by MEG.

Fundamental issues in fluid modeling: direct substitution and aliasing methods.

It is shown how the accuracy of fluid models of charged particles in gases can be improved significantly by direct substitution of swarm transport coefficient data, rather than cross sections, into the average collision terms. This direct substitution method emerges in a natural way for fluid formulations in which the role of the mean energy is transparent, whatever the mass of the charged particles in equation (ions or electrons), and requires no further approximations. The procedure is illustrated by numerical examples for electrons, including the operational window of E/N for an idealized Franck-Hertz experiment. Using the same fluid formulation, we develop an aliasing method to estimate otherwise unknown mobility data for one type of particle, from known mobility data for another type of particle. The method is illustrated for muons in hydrogen, using tabulated data for protons in the same gas.

New limit on the lepton-flavor-violating decay µ+→e+γ.

We present a new result based on an analysis of the data collected by the MEG detector at the Paul Scherrer Institut in 2009 and 2010, in search of the lepton-flavor-violating decay µ(+)e(+)γ. The likelihood analysis of the combined data sample, which corresponds to a total of 1.8×10(14) muon decays, gives a 90% C.L. upper limit of 2.4×10(-12) on the branching ratio of the µ(+)→e(+)γ decay, constituting the most stringent limit on the existence of this decay to date.

[Personal contextual factors of the ICF draft from the Working Group "ICF" of Specialty Group II of the Geman Society for Social Medicine and Prevention]. / Personbezogene Faktoren der ICF - Entwurf der AG "ICF" des Fachbereichs II der Deutschen Gesellschaft für Sozialmedizin und Prävention (DGSMP).

Personal contextual factors play an essential part in the ICF model in relation to patient-centred care. It is generally assumed that their classification must refer to the country-specific social and cultural setting and its particular linguistic terms. Therefore personal factors are not classified as yet by the WHO for general use. In Germany in 2006 a group of experts working on the medical advisory board of statutory health insurance published a proposal for a systematic classification of relevant personal factors to describe the background of an individual's life and living. This classification was now further analysed and thoroughly revised by a more comprehensive group of German specialists working in different health care insurances and institutions, authorised by the German Society for Social Medicine and Prevention (DGSMP), supported by German-speaking Swiss ICF specialists. This classification is published as work in progress intending to broaden and prepare the process of discussion for a consensus conference to be held in Germany in 2011.

Relevance of an academic GMP Pan-European vector infra-structure (PEVI).

In the past 5 years, European investigators have played a major role in the development of clinical gene therapy. The provision of substantial funds by some individual member states to construct GMP facilities makes it an opportune time to network available gene therapy GMP facilities at an EU level. The integrated coordination of GMP production facilities and human skills for advanced gene and genetically-modified (GM) cell therapy, can dramatically enhance academic-led "First-in-man" gene therapy trials. Once proof of efficacy is gathered, technology can be transferred to the private sector which will take over further development taking advantage of knowledge and know-how. Complex technical challenges require existing production facilities to adapt to emerging technologies in a coordinated manner. These include a mandatory requirement for the highest quality of production translating gene-transfer technologies with pharmaceutical-grade GMP processes to the clinic. A consensus has emerged on the directions and priorities to adopt, applying to advanced technologies with improved efficacy and safety profiles, in particular AAV, lentivirus-based and oncolytic vectors. Translating cutting-edge research into "First-in-man" trials require that pre-normative research is conducted which aims to develop standard assays, processes and candidate reference materials. This research will help harmonise practices and quality in the production of GMP vector lots and GM-cells. In gathering critical expertise in Europe and establish conditions for interoperability, the PEVI infrastructure will contribute to the demands of the advanced therapy medicinal products* regulation and to both health and quality of life of EU-citizens.

Hsa-miR-9 methylation status is associated with cancer development and metastatic recurrence in patients with clear cell renal cell carcinoma.

The long-term prognosis for clear cell renal cell carcinoma (ccRCC) is dramatically altered by the development of metastatic recurrence. However, there are very few indicators that can predict which patient will develop a recurrence. MicroRNAs regulate many cellular processes and have been shown to be associated with cancer development and recurrence. More recently it has been shown that microRNA genes can be epigenetically modified in cancer, resulting in aberrant silencing of microRNA genes with tumor suppressor functions. In this study, we show that two genes encoding for hsa-miR-9 are significantly hypermethylated in ccRCC tumors compared with adjacent normal tissues (P-value <0.001 for both miR-9-1 and miR-9-3) resulting in decreased expression, and that the methylation of these genes was more significant in DNA obtained from the primary tumor for patients who developed a recurrence (P-value: 0.012 and 0.009 for miR-9-1 and miR-9-3, respectively) than in tumors from nonrecurrent patients. Furthermore, methylation of miR-9-3 was significantly associated with an increased risk of recurrence (hazard ratio: 5.85, 95% confidence intervals: 1.30-26.35) and high methylation levels of either miR-9-1 or miR-9-3 resulted in a significant, nearly 30-month decrease in recurrence-free survival time (P-value: 0.034 and 0.007 for miR-9-1 and miR-9-3, respectively). Our results demonstrate that hsa-miR-9 is involved in the development of ccRCC while also having a role in the development of metastatic recurrence.

[Hematopoietic growth factors. Possibilities and limitations]. / Hämatopoetische Wachstumsfaktoren. Möglichkeiten und Grenzen.

The production of hematopoietic cells is under the tight control of distinct growth factors. As therapeutic agents, granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and thrombopoiesis-stimulating agents (TSA) are in routine clinical use. Granulocyte colony-stimulating factor is used to prevent febrile neutropenia or to increase dose-density in chemotherapy regimens. Despite a reduced duration of neutropenia, randomized controlled trials have documented only a modest clinical benefit. A clinical advantage of dose-dense chemotherapy has been shown only in specific chemotherapy regimens. Clinical practice guidelines recommend the use of G-CSF for patients with a high risk of adverse outcome of febrile neutropenia. Erythropoiesis-stimulating agents (ESAs) are used as an alternative to blood transfusion in patients with chemotherapy-induced anemia. However, recent meta-analyses of clinical studies suggest that their use was associated with an increased risk of all-cause mortality and serious adverse events. Thrombopoiesis-stimulating agents have been introduced recently into the market for patients with immune thrombocytopenic purpura. Prior to the use of TSA in other conditions such as chemotherapy-induced thrombocytopenia the lessons learned with G-CSF and ESAs should be taken into account.

Clinical prediction of postoperative seizure control: structural, functional findings and disease histories.

OBJECTIVE: Mesial temporal lobe epilepsy (MTLE) constitutes a heterogenic entity with different clinical histories, pathomorphological hippocampal findings and varying postoperative outcome. METHOD: 64 patients with MTLE, scheduled for hippocampal resection, were included. Initial precipitating injuries (IPI), structural and functional findings and neuropathological classification of hippocampal specimens were related to prediction of surgical outcome. RESULTS: Patients with severe hippocampal sclerosis (mesial temporal sclerosis (MTS) type 1b) became completely seizure free (80% Engel Ia) significantly more often compared with approximately 40% of seizure freedom in other types of MTS or in patients without hippocampal cell loss (non-MTS), irrespective of the extent of hippocampal resection. Age at IPI was found to be related to MTS variants (p<0.01) and significantly correlated with cell loss in the CA1 sector and the dentate gyrus (p<0.05). Presurgical MRI discriminated between MTS and non-MTS, but did not discriminate between different MTS subtypes. The most reliable predictors of MTS type 1b were the Wada memory scores combined with interictal and ictal EEG. CONCLUSIONS: A particular cohort of MTLE patients benefit most from surgical treatment. These patients are clinically best recognised as presenting with (1) very early IPI; (2) a silent period of about 5 years; (3) unequivocal unilateral EEG localisation; (4) MRI signs of MTS; and (5) Wada Test indicates contralateral memory compensation and ipsilateral reduced memory capacity. MTS type 1b, characterised by severe cell loss in all hippocampal subfields including the dentate gyrus, and associated with optimal postoperative seizure control, was preoperatively clinically best differentiated from other MTS types by the Wada Memory Test.