Leveraging gene expression subgroups to classify DLBCL patients and select for clinical benefit from a novel agent

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, commonly described by cell-of-origin (COO) molecular subtypes. We sought to identify novel patient subgroups through an unsupervised analysis of a large public dataset of gene expression profiles from newly diagnosed de novo DLBCL patients, yielding 2 biologically distinct subgroups characterized by differences in the tumor microenvironment. Pathway analysis and immune deconvolution algorithms identified higher B-cell content and a strong proliferative signal in subgroup A and enriched T-cell, macrophage, and immune/inflammatory signals in subgroup B, reflecting similar biology to published DLBCL stratification research. A gene expression classifier, featuring 26 gene expression scores, was derived from the public dataset to discriminate subgroup A (classifier-negative, immune-low) and subgroup B (classifier-positive, immune-high) patients. Subsequent application to an independent series of diagnostic biopsies replicated the subgroups, with immune cell composition confirmed via immunohistochemistry. Avadomide, a CRL4CRBN E3 ubiquitin ligase modulator, demonstrated clinical activity in relapsed/refractory DLBCL patients, independent of COO subtypes. Given the immunomodulatory activity of avadomide and the need for a patient-selection strategy, we applied the gene expression classifier to pretreatment biopsies from relapsed/refractory DLBCL patients receiving avadomide (NCT01421524). Classifier-positive patients exhibited an enrichment in response rate and progression-free survival of 44% and 6.2 months vs 19% and 1.6 months for classifier-negative patients (hazard ratio, 0.49; 95% confidence interval, 0.280-0.86; P = .0096). The classifier was not prognostic for rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone or salvage immunochemotherapy. The classifier described here discriminates DLBCL tumors based on tumor and nontumor composition and has potential utility to enrich for clinical response to immunomodulatory agents, including avadomide

Exceptional skull of huayqueriana (mammalia, litopterna, macraucheniidae) from the late miocene of Argentina: Anatomy, systematics, and peleobiological implications

The Huayquerías Formation (Late Miocene, Huayquerian SALMA) is broadly exposed in westcentral Argentina (Mendoza). The target of several major paleontological expeditions in the first half of the 20th century, the Mendozan Huayquerías (badlands) have recently yielded a significant number of new fossil finds. In this contribution we describe a complete skull (IANIGLA-PV 29) and place it systematically as Huayqueriana cf. H. cristata (Rovereto, 1914) (Litopterna, Macraucheniidae). The specimen shares some nonexclusive features with H. cristata (similar size, rostral border of the orbit almost level with distal border of M3, convergence of maxillary bones at the level of the P3/P4 embrasure, flat snout, very protruding orbits, round outline of premaxillary area in palatal view, and small diastemata between I3/C and C/P1). Other differences (e.g., lack of sagittal crest) may or may not represent intraspecific variation. In addition to other features described here, endocast reconstruction utilizing computer tomography (CT) revealed the presence of a derived position of the orbitotemporal canal running below the rhinal fissure along the lateroventral aspect of the piriform lobe. CT scanning also established that the maxillary nerve (CN V2) leaves the skull through the sphenoorbital fissure, as in all other litopterns, a point previously contested for macraucheniids. The angle between the lateral semicircular canal and the plane of the base of the skull is about 26°, indicating that in life the head was oriented much as in modern horses. Depending on the variables used, estimates of the body mass of IANIGLA-PV 29 produced somewhat conflicting results. Our preferred body mass estimate is 250 kg, based on the centroid size of 36 3D cranial landmarks and accompanying low prediction error. The advanced degree of tooth wear in IANIGLA-PV 29 implies that the individual died well into old age. However, a count of cementum lines on the sectioned left M2 is consistent with an age at death of 10 or 11 years, younger than expected given its body mass. This suggests that the animal had a very abrasive diet. Phylogenetic analysis failed to resolve the position of IANIGLA-PV 29 satisfactorily, a result possibly influenced by intraspecific variation. There is no decisive evidence for the proposition that Huayqueriana, or any other litoptern, were foregut fermenters.Fil: Forasiepi, Analia Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: MacPhee, Ross D. E.. American Museum Of Natural History; Estados UnidosFil: Hernández del Pino, Santiago Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Schmidt, Gabriela Ines. Provincia de Entre Ríos. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción. Universidad Autónoma de Entre Ríos. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción; ArgentinaFil: Amson, Eli. Universitat Zurich; SuizaFil: Grohé, Camille. American Museum Of Natural History; Estados Unido

Internal representations of smell in the Drosophila brain

Recent advances in sensory neuroscience using Drosophila olfaction as a model system have revealed brain maps representing the external world. Once we understand how the brain's built-in capability generates the internal olfactory maps, we can then elaborate how the brain computes and makes decision to elicit complex behaviors. Here, we review current progress in mapping Drosophila olfactory circuits and discuss their relationships with innate olfactory behaviors

Recommendations for the introduction of metagenomic next-generation sequencing in clinical virology, part II: bioinformatic analysis and reporting

Metagenomic next-generation sequencing (mNGS) is an untargeted technique for determination of microbial DNA/RNA sequences in a variety of sample types from patients with infectious syndromes. mNGS is still in its early stages of broader translation into clinical applications. To further support the development, implementation, optimization and standardization of mNGS procedures for virus diagnostics, the European Society for Clinical Virology (ESCV) Network on Next-Generation Sequencing (ENNGS) has been established. The aim of ENNGS is to bring together professionals involved in mNGS for viral diagnostics to share methodologies and experiences, and to develop application guidelines. Following the ENNGS publication Recommendations for the introduction of mNGS in clinical virology, part I: wet lab procedure in this journal, the current manuscript aims to provide practical recommendations for the bioinformatic analysis of mNGS data and reporting of results to clinicians.Molecular basis of virus replication, viral pathogenesis and antiviral strategie

Spin alignment of leading K∗(892)0K^{*}(892)^{0} mesons in hadronic Z0Z^0 decays

Helicity density matrix elements for inclusive K*(892)^0 mesons from hadronic Z^0 decays have been measured over the full range of K^*0 momentum using data taken with the OPAL experiment at LEP. A preference for occupation of the helicity zero state is observed at all scaled momentum x_p values above 0.3, with the matrix element rho_00 rising to 0.66 +/- 0.11 for x_p > 0.7. The values of the real part of the off-diagonal element rho_1-1 are negative at large x_p, with a weighted average value of -0.09 +/- 0.03 for x_p > 0.3, in agreement with new theoretical predictions based on Standard Model parameters and coherent fragmentation of the qq(bar) system from the Z^0 decay. All other helicity density matrix elements measured are consistent with zero over the entire x_p range. The K^*0 fragmentation function has also been measured and the total rate determined to be 0.74 +/- 0.02 +/- 0.02 K*(892)^0 mesons per hadronic Z^0 decay.Helicity density matrix elements for inclusive K*(892)^0 mesons from hadronic Z^0 decays have been measured over the full range of K^*0 momentum using data taken with the OPAL experiment at LEP. A preference for occupation of the helicity zero state is observed at all scaled momentum x_p values above 0.3, with the matrix element rho_00 rising to 0.66 +/- 0.11 for x_p > 0.7. The values of the real part of the off-diagonal element rho_1-1 are negative at large x_p, with a weighted average value of -0.09 +/- 0.03 for x_p > 0.3, in agreement with new theoretical predictions based on Standard Model parameters and coherent fragmentation of the qq(bar) system from the Z^0 decay. All other helicity density matrix elements measured are consistent with zero over the entire x_p range. The K^*0 fragmentation function has also been measured and the total rate determined to be 0.74 +/- 0.02 +/- 0.02 K*(892)^0 mesons per hadronic Z^0 decay.Helicity density matrix elements for inclusive K*(892)^0 mesons from hadronic Z^0 decays have been measured over the full range of K^*0 momentum using data taken with the OPAL experiment at LEP. A preference for occupation of the helicity zero state is observed at all scaled momentum x_p values above 0.3, with the matrix element rho_00 rising to 0.66 +/- 0.11 for x_p > 0.7. The values of the real part of the off-diagonal element rho_1-1 are negative at large x_p, with a weighted average value of -0.09 +/- 0.03 for x_p > 0.3, in agreement with new theoretical predictions based on Standard Model parameters and coherent fragmentation of the qq(bar) system from the Z^0 decay. All other helicity density matrix elements measured are consistent with zero over the entire x_p range. The K^*0 fragmentation function has also been measured and the total rate determined to be 0.74 +/- 0.02 +/- 0.02 K*(892)^0 mesons per hadronic Z^0 decay.Helicity density matrix elements for inclusive K*(892)^0 mesons from hadronic Z^0 decays have been measured over the full range of K^*0 momentum using data taken with the OPAL experiment at LEP. A preference for occupation of the helicity zero state is observed at all scaled momentum x_p values above 0.3, with the matrix element rho_00 rising to 0.66 +/- 0.11 for x_p > 0.7. The values of the real part of the off-diagonal element rho_1-1 are negative at large x_p, with a weighted average value of -0.09 +/- 0.03 for x_p > 0.3, in agreement with new theoretical predictions based on Standard Model parameters and coherent fragmentation of the qq(bar) system from the Z^0 decay. All other helicity density matrix elements measured are consistent with zero over the entire x_p range. The K^*0 fragmentation function has also been measured and the total rate determined to be 0.74 +/- 0.02 +/- 0.02 K*(892)^0 mesons per hadronic Z^0 decay.Helicity density matrix elements for inclusive K ∗ (892) 0 mesons from hadronic Z 0 decays have been measured over the full range of K ∗ 0 momentum using data taken with the OPAL experiment at LEP. A preference for occupation of the helicity zero state is observed at all scaled momentum x p values above 0.3, with the matrix element ϱ 00 rising to 0.66 ± 0.11 for x p > 0.7. The values of the real part of the off-diagonal element ϱ 1 - 1 are negative at large x p , with a weighted average value of −0.09 ± 0.03 for x p > 0.3, in agreement with new theoretical predictions based on Standard Model parameters and coherent fragmentation of the q q system from the Z 0 decay. All other helicity density matrix elements measured are consistent with zero over the entire x p range. The K ∗ 0 fragmentation function has also been measured and the total rate determined to be 0.74 ± 0.02 ± 0.02 K ∗ (892) 0 mesons per hadronic Z 0 decay

The On-orbit Calibrations for the Fermi Large Area Telescope

The Large Area Telescope (LAT) on--board the Fermi Gamma ray Space Telescope began its on--orbit operations on June 23, 2008. Calibrations, defined in a generic sense, correspond to synchronization of trigger signals, optimization of delays for latching data, determination of detector thresholds, gains and responses, evaluation of the perimeter of the South Atlantic Anomaly (SAA), measurements of live time, of absolute time, and internal and spacecraft boresight alignments. Here we describe on orbit calibration results obtained using known astrophysical sources, galactic cosmic rays, and charge injection into the front-end electronics of each detector. Instrument response functions will be described in a separate publication. This paper demonstrates the stability of calibrations and describes minor changes observed since launch. These results have been used to calibrate the LAT datasets to be publicly released in August 2009.Comment: 60 pages, 34 figures, submitted to Astroparticle Physic