First-principle computations of ferromagnetic HgCr2Z4 (Z = S, Se) spinels for spintronic and energy storage system applications

We explored electronic spin-dependent physical aspects of ferromagnetic HgCr2Z4 (Z = S, Se) spinels using density functional theory (DFT) for spintronic and energy storage applications. In calculations of structural, electronic, magnetic, and transport aspects, we used Perdew-Burke-Ernzerhof generalized gradient approximation (PBEsol GGA) plus modified Becke-Johnson (mBJ) potential. To calculate structural parameters, we optimized both spinels in the ferromagnetic phase and our predicted data of structural parameters show good comparison with existing experimental data. Also, the calculated negative formation energy confirms the structural stability of the studied spinels. Analyzingferromagnetic nature of studied spinels based on exchange splitting energy and magnetic parameters, we used mBJ potential to calculate band structure (BS) and density of states (DOS). By exploring DOS, we found the dominant role of electrons spin has been shown by negative indirect exchange energy Δx(pd) values and the fulfillment of the condition Δx(d) >ΔEcry. In addition, exchange constants (N0α and N0β) and magnetic moments were also calculated to ensure their ferromagnetism in studied spinels. Further, the exploration for the influence of electrons spin on electronic transport aspects has been done by investigating electrical and thermal conductivities, Seebeck coefficient, and power factor by using classical Boltzmann transport theory

Central memory phenotype drives success of checkpoint inhibition in combination with CAR T cells

The immunosuppressive microenvironment in solid tumors is thought to form a barrier to the entry and efficacy of cell-based therapies such as chimeric antigen receptor (CAR) T cells. Combining CAR T cell therapy with checkpoint inhibitors has been demonstrated to oppose immune escape mechanisms in solid tumors and augment antitumor efficacy. We evaluated PD-1/PD-L1 signaling capacity and the impact of an inhibitor of this checkpoint axis in an in vitro system for cancer cell challenge, the coculture of L1CAM-specific CAR T cells with neuroblastoma cell lines. Fluorescence-activated cell sorting-based analyses and luciferase reporter assays were used to assess PD-1/PD-L1 expression on CAR T and tumor cells as well as CAR T cell ability to kill neuroblastoma cells. Coculturing neuroblastoma cell lines with L1CAM-CAR T cells upregulated PD-L1 expression on neuroblastoma cells, confirming adaptive immune resistance. Exposure to neuroblastoma cells also upregulated the expression of the PD-1/PD-L1 axis in CAR T cells. The checkpoint inhibitor, nivolumab, enhanced L1CAM-CAR T cell-directed killing. However, nivolumab-enhanced L1CAM-CAR T cell killing did not strictly correlate with PD-L1 expression on neuroblastoma cells. In fact, checkpoint inhibitor success relied on strong PD-1/PD-L1 axis expression in the CAR T cells, which in turn depended on costimulatory domains within the CAR construct, and more importantly, on the subset of T cells selected for CAR T cell generation. Thus, T cell subset selection for CAR T cell generation and CAR T cell prescreening for PD-1/PD-L1 expression could help determine when combination therapy with checkpoint inhibitors could improve treatment efficacy

Tumor-Derived Extracellular Vesicles Impair CD171-Specific CD4+ CAR T Cell Efficacy

Chimeric antigen receptor (CAR) T cell efficacy against solid tumors is currently limited by several immune escape mechanisms, which may include tumor-derived extracellular vesicles. Advanced neuroblastoma is an aggressive childhood tumor without curative treatment options for most relapsed patients today. We here evaluated the role of tumor-derived extracellular vesicles on the efficacy of CAR T cells targeting the neuroblastoma-specific antigen, CD171. For this purpose, CAR T cell activation, cytokine production, exhaustion, and tumor cell-directed cytotoxicity upon co-culture was evaluated. Tumor-derived extracellular vesicles isolated from SH-SY5Y neuroblastoma cells neither affected CAR T cell activation nor expression of inhibitory markers. Importantly, exposure of CD4+ CD171-specific CAR T cells to tumor-derived extracellular vesicles significantly impaired tumor cytotoxicity of CAR T cells. This effect was independent of neurotrophic receptor tyrosine kinases 1 or 2 (NTRK1, NTRK2) expression, which is known to impact immune responses against neuroblastoma. Our results demonstrate for the first time the impact of tumor-derived extracellular vesicles and non-cell-mediated tumor-suppressive effects on CD4+ CAR T cell efficacy in a preclinical setting. We conclude that these factors should be considered for any CAR T cell-based therapy to make CAR T cell therapy successful against solid tumors

Operation and performance of the ATLAS Tile Calorimeter in Run 1

The Tile Calorimeter is the hadron calorimeter covering the central region of the ATLAS experiment at the Large Hadron Collider. Approximately 10,000 photomultipliers collect light from scintillating tiles acting as the active material sandwiched between slabs of steel absorber. This paper gives an overview of the calorimeter’s performance during the years 2008–2012 using cosmic-ray muon events and proton–proton collision data at centre-of-mass energies of 7 and 8TeV with a total integrated luminosity of nearly 30 fb−1. The signal reconstruction methods, calibration systems as well as the detector operation status are presented. The energy and time calibration methods performed excellently, resulting in good stability of the calorimeter response under varying conditions during the LHC Run 1. Finally, the Tile Calorimeter response to isolated muons and hadrons as well as to jets from proton–proton collisions is presented. The results demonstrate excellent performance in accord with specifications mentioned in the Technical Design Report

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Selective impact of neuroblastoma-derived extracellular vesicles on CD4+ CD171-specific CAR T cell efficacy against NTRK expressing neuroblastoma cell lines

Chimeric antigen receptor (CAR) T cell therapy decribes the genetic introduction of a tumor specific CAR construct into patient derived T cells in order to reinforce tumor specific cytotoxic responses. This has shown great success in hematological malignancies, whereas for solid tumors similar success has yet to be achieved. CAR T cell therapy in solid tumors is aggravated through multiple factors related to the imminent and distant tumor microenvironment. Neuroblastoma makes up a large part of pediatric cancer deaths, as it is most commonly diagnosed in advanced stages, which limits currently available curative treatment options. The expression of immunogenic tumor surface antigens such as neurotrophic receptor kinases 1 and 2 (NTRK1, NTRK2) have shown to play a leading role in neuroblastoma biology. Another way neuroblastoma and solid tumors in general exert their immunoescape mechanisms is through tumor-derived extracellular vesicles across distant cell sites. CD171 is an abundant neuroblastoma-specific surface molecule that is targeted by CD171-specific CAR T cells. CD171-CAR T cells of CD4+ and CD8+ subgroups were evaluated in co-culture experiments with an SH-SY5Y neuroblastoma cell line model to assess CAR T cell cytotoxicity, activation, inhibition and cytokine production. We observed concurrent effects with NTRK1 or NTRK2 expression in neuroblastoma on CAR T cell cytotoxicity. NTRK1 expression improved cytotoxicity in both CD171-specific CAR T cell subgroups. We evaluated the isolated role of neuroblastoma derived extracellular vesicles by co-culture with the CD171-CAR T cells prior to tumor cell co-culture. This had no influence on CAR T cell viability, activation or cytokine production, yet SH-SY5Y derived extracellular vesicles impaired CD171-CAR T cell cytotoxicity of the CD4+ subgroup significantly, independent of NTRK1 or NTRK2 expression. For the first time, our findings demonstrate the influence of tumor-derived extracellular vesicles and non-cell-mediated tumor-suppressive effects on the efficacy of CD4+ CAR T cells in a preclinical setting. We conclude that for the development of CAR T cell-based treatments, these variables should be considered to improve CAR T cell therapy effectiveness against solid tumors.Chimerische Antigenrezeptor (CAR) T Zelltherapie basiert auf der genetischen Integration eines tumorspezifischen CAR-Konstruktes in Patienten eigene T-Zellen, um tumorspezifische zytotoxische Reaktionen zu verstärken. Bei hämatologischen Malignitäten hat dies große Erfolge erzielt, während bei soliden Tumoren ein ähnlicher Erfolg noch ausgebleibt. Die CAR-T-Zelltherapie bei soliden Tumoren wird durch Faktoren erschwert, die mit dem direkten, aber auch entfernten Tumormicromilieu zusammenhängen. Das Neuroblastom macht einen großen Teil der pädiatrisch-onkologischen Todesfälle aus, da es meistens in bereits fortgeschrittenen Stadien diagnostiziert wird, was die verfügbaren Möglichkeiten zur kurativen Behandlung stark einschränkt. Die Expression immunogener Tumoroberflächenantigene, wie der Neurotrophen Rezeptorkinasen 1 und 2 (NTRK1, NTRK2) spielen eine führende Rolle in der Neuroblastombiologie. Neuroblastome und solide Tumoren im Allgemeinen schützen sich vor dem Immunsystem durch die Produktion und den weitrechenden Einfluss von extrazellulären Vesikeln. CD171 ist ein reichlich exprimiertes Neuroblastom-spezifisches Oberflächenantigen und das Ziel von CD171-spezifischen CAR-T-Zellen. Wir untersuchten die Zytotoxizität, Aktivierung, Erschöpfung und Zytokinproduktion von CD171-CAR-T-Zellen aus CD4+- und CD8+-Fraktionen nach Kokulturen mit einem SH-SY5Y-Neuroblastom-Zelllinienmodell. Wir beobachteten kongruente Effekte von NTRK1- oder NTRK2-Expression in Neuroblastomzellen auf die Effizienz von CAR-T-Zellen. Die NTRK1-Expression verbesserte die Zytotoxizität in beiden CD171-CAR-T-Zellfraktionen. Wir untersuchten ebenfalls die spezifischen Effekte von Tumorvesikeln unserer Neuroblastomzellen durch vorausgehender Kokultur mit den CD171-CAR-T-Zellen und darauffolgender Kokultur mit den entsprechenden Tumorzellen. Vorausgehender Kontakt mit den Neuroblastomvesikeln hatte keinen Einfluss auf die Viabilität, Aktivierung oder Zytokinproduktion von CAR T-Zellen, jedoch beeinträchtigte vorausgehende Kokultur mit SH-SY5Y Vesikeln die Zytotoxizität von CD171-CAR-T-Zellen der CD4+-Fraktion signifikant, unabhängig von NTRK1- oder NTRK2-Expression. Unsere Ergebnisse zeigen zum ersten Mal den Einfluss von extrazellulären Tumorvesikeln und nicht zellvermittelten tumorsuppressiven Effekten auf die Wirksamkeit von CD4+ CD171-spezifischen CAR-T Zellen in einem präklinischen Setting. Wir schließen daraus, dass bei der Entwicklung von CAR T-Zelltherapien diese Variablen berücksichtigt werden sollten, um die Wirksamkeit der CAR T-Zellen gegen solide Tumoren zu verbessern

Att växa upp i förorten : En kvalitativ studie om unga killars livsvillkor och tillhörighet i Hjällbo

Syftet med denna studie är att undersöka hur åtta unga killars livsvillkor och tillhörighet påverkas av att bo i Hjällbo. Detta genom att förstå deras upplevelser av omvärlden och medias syn på ungdomarna och bostadsområdet och om detta har någon påverkan på deras framtida förutsättningar i livet. Vi använde oss av en kvalitativ metod där vi utgick från hermeneutiken som metodansats. Vi utförde åtta semistrukturerade intervjuer och materialet vi fick in av intervjuerna analyserades med begrepp som Stigma (Goffman), Territoriell stigmatisering (Sernhede), Tillhörighet (May) och Identitet (Jenkins). Resultatet visar att ungdomarnas livsvillkor påverkas av att de har sämre förutsättningar i livet, bland annat svårigheter att få jobb. De unga killarna upplevde att utbildning inte är av betydelse eftersom de upplever att omvärlden sätter fokus på stigman de bär på och inte kvalifikationer. De unga killarna upplever att omvärlden och media har skapat en bild av området och de ungdomar som bor där som inte stämmer överens med verkligheten. De unga killarna upplever en stark tillhörighet i förorten.