Efficient preclinical treatment of cortical T cell acute lymphoblastic leukemia with T lymphocytes secreting anti-CD1a T cell engagers

BACKGROUND: The dismal clinical outcome of relapsed/refractory (R/R) T cell acute lymphoblastic leukemia (T-ALL) highlights the need for innovative targeted therapies. Although chimeric antigen receptor (CAR)-engineered T cells have revolutionized the treatment of B cell malignancies, their clinical implementation in T-ALL is in its infancy. CD1a represents a safe target for cortical T-ALL (coT-ALL) patients, and fratricide-resistant CD1a-directed CAR T cells have been preclinically validated as an immunotherapeutic strategy for R/R coT-ALL. Nonetheless, T-ALL relapses are commonly very aggressive and hyperleukocytic, posing a challenge to recover sufficient non-leukemic effector T cells from leukapheresis in R/R T-ALL patients. METHODS: We carried out a comprehensive study using robust in vitro and in vivo assays comparing the efficacy of engineered T cells either expressing a second-generation CD1a-CAR or secreting CD1a x CD3 T cell-engaging Antibodies (CD1a-STAb). RESULTS: We show that CD1a-T cell engagers bind to cell surface expressed CD1a and CD3 and induce specific T cell activation. Recruitment of bystander T cells endows CD1a-STAbs with an enhanced in vitro cytotoxicity than CD1a-CAR T cells at lower effector:target ratios. CD1a-STAb T cells are as effective as CD1a-CAR T cells in cutting-edge in vivo T-ALL patient-derived xenograft models. CONCLUSIONS: Our data suggest that CD1a-STAb T cells could be an alternative to CD1a-CAR T cells in coT-ALL patients with aggressive and hyperleukocytic relapses with limited numbers of non-leukemic effector T cellsResearch in LA-V laboratory is funded by the Spanish Ministry of Science and Innovation (PID2020-117323RB-100 and PDC2021-121711-100), and the Carlos III Health Institute (DTS20/00089), with European Regional Development Fund (FEDER) cofinancing; the Spanish Association Against Cancer (AECC PROYE19084ALVA) and the CRIS Cancer Foundation (FCRIS-2018-0042 and FCRIS2021-0090). Research in PM laboratory is supported by CERCA/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa for core support; 'la Caixa' Foundation under the agreement LCF/PR/HR19/52160011; the European Research Council grant (ERC-PoC-957466); the Spanish Ministry of Science and Innovation (PID2019-108160RB-I00); and the ISCIII-RICORS within the Next Generation EU program (plan de Recuperación, Transformación y Resilencia). MLT is supported by Spanish Ministry of Science and Innovation (PID2019-105623RB-I00) and the Spanish Association Against Cancer (CICPF18030TORI). PP is supported by Carlos III Health Institute (PI21-01834), with FEDER cofinancing and Fundación Ramón Areces. NT was supported by an FPU PhD fellowship from Spain's Ministerio de Universidades (FPU19/00039). OH was supported by an industrial PhD fellowship from the Comunidad de Madrid (IND2020/BMD-17668). LD-A was supported by a Rio Hortega fellowship from the Carlos III Health Institute (CM20/00004). VMD is supported by the Torres Quevedo subprogram of the State Research Agency of the Ministry of Science, Innovation and Universities (Ref. PTQ2020-011056). DSM is partially founded by a Sara Borrell fellowship from Carlos III Health Institute (CD19/00013

San Adrian: un nuevo yacimiento de la Edad del Bronce en el Norte de la Peninsula Iberica

Bronze Age studies carried out in the Cantabrian Region have traditionally focused on prestige goods and funerary contexts. As a result of this, the lack of information about daily activities, subsistence strategies, and human settlement on a regional scale is evident in the state of art. However, current research has achieved new discoveries in recent years, allowing a reconstruction of some aspects of the economic structure, settlements, material culture and the palaeoenvironment during the Bronze Age. Indeed, besides the funerary practices discovered in 1983 in San Adrian (Parztuergo Nagusia, Gipuzkoa), research has now revealed the presence of Upper Palaeolithic and Early Bronze Age occupations. This paper presents a first characterization of the retrieved evidence and a preliminary evaluation of the archaeological site and its environment. San Adrian is a tunnel-shaped cave located at 1,000 meters a.s.l. in the Aizkorri mountain range, opening a passage beneath the Atlantic-Mediterranean watershed in northern Iberia. The strategic character of this mountain site is demonstrated by the presence of Upper Palaeolithic and Bronze Age occupations, and by the construction of a road passing through it and the fortification of both its entrances in the Middle Ages. The aim of the archaeological survey started in 2008 was to identify, describe and evaluate the heritage potential of the cave, because previous fieldwork had only managed to make surface finds in the side galleries, including a medieval hoard and Bronze Age human remains. The work carried out by our research group at San Adrian includes a series of test pits and the excavation of an area nine square metres in size following stratigraphic criteria. In the current state, we identified at least two contexts corresponding to Late Upper Palaeolithic and Bronze Age occupations in the cave. Fieldwork included the sieving and flotation of sediment and the collection of samples for different types of analysis: palynology, carpology, sedimentology, and radiocarbon dating. The evidence is being studied by a multidisciplinary team according to expertise requirements for each topic: palaeobotany and environment, archaeozoology, sedimentology, geology, physical anthropology, prehistoric industries (lithics, pottery and bone) and archaeological and historical documentation. Because of its recent discovery, Upper Palaeolithic evidence remains still under study, but first results on Bronze Age layers can be presented. The ongoing archaeobotanical and archaeozoological studies reveal the exploitation of domestic plants and fauna complemented by hunting and foraging of wild species. At the same time, the archaeological artefacts and their production sequences show the exploitation of nearby resources on both sides of the mountain range, while prestige goods are absent. This evidence is also used to estimate the regularity of cave occupations and to propose a model of seasonal exploitation of the mountain environment. The results obtained reveal the exploitation of resources from both the Mediterranean and Atlantic basins, and contribute towards an understanding of the daily activities of Bronze Age societies. In addition, the evidence shows the exchange and circulation of quotidian products between the Cantabrian region and inland Iberia in other networks than those of prestige goods

Genome-wide multi-trait analysis of irritable bowel syndrome and related mental conditions identifies 38 new independent variants

Irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction frequently accompanied by mental conditions, including depression and anxiety. Despite showing substantial heritability and being partly determined by a genetic component, the genetic underpinnings explaining the high rates of comorbidity remain largely unclear and there are no conclusive data on the temporal relationship between them. Exploring the overlapping genetic architecture between IBS and mental conditions may help to identify novel genetic loci and biological mechanisms underlying IBS and causal relationships between them. We quantified the genetic overlap between IBS, neuroticism, depression and anxiety, conducted a multi-trait genome-wide association study (GWAS) considering these traits and investigated causal relationships between them by using the largest GWAS to date. IBS showed to be a highly polygenic disorder with extensive genetic sharing with mental conditions. Multi-trait analysis of IBS and neuroticism, depression and anxiety identified 42 genome-wide significant variants for IBS, of which 38 are novel. Fine-mapping risk loci highlighted 289 genes enriched in genes upregulated during early embryonic brain development and gene-sets related with psychiatric, digestive and autoimmune disorders. IBS-associated genes were enriched for target genes of anti-inflammatory and antirheumatic drugs, anesthetics and opioid dependence pharmacological treatment. Mendelian-randomization analysis accounting for correlated pleiotropy identified bidirectional causal effects between IBS and neuroticism and depression and causal effects of the genetic liability of IBS on anxiety. These findings provide evidence of the polygenic architecture of IBS, identify novel genome-wide significant variants for IBS and extend previous knowledge on the genetic overlap and relationship between gastrointestinal and mental disorders. The online version contains supplementary material available at 10.1186/s12967-023-04107-5

Monovision-based vehicle detection, distance and relative speed measurement in urban traffic

This study presents a monovision-based system for on-road vehicle detection and computation of distance and relative speed in urban traffic. Many works have dealt with monovision vehicle detection, but only a few of them provide the distance to the vehicle which is essential for the control of an intelligent transportation system. The system proposed integrates a single camera reducing the monetary cost of stereovision and RADAR-based technologies. The algorithm is divided in three major stages. For vehicle detection, the authors use a combination of two features: the shadow underneath the vehicle and horizontal edges. They propose a new method for shadow thresholding based on the grey-scale histogram assessment of a region of interest on the road. In the second and third stages, the vehicle hypothesis verification and the distance are obtained by means of its number plate whose dimensions and shape are standardised in each country. The analysis of consecutive frames is employed to calculate the relative speed of the vehicle detected. Experimental results showed excellent performance in both vehicle and number plate detections and in the distance measurement, in terms of accuracy and robustness in complex traffic scenarios and under different lighting conditions

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum