Outcome of Patients with Diffuse Large B-Cell Lymphoma Relapsing after Autologous Transplant before Availability of CAR-T Cell Treatment.

INTRODUCTION Autologous stem cell transplantation (ASCT) following high-dose chemotherapy is applied as salvage therapy in patients with relapsed disease or as first-line consolidation in high-risk DLBCL with chemo-sensitive disease. However, the prognosis of relapsing DLBCL post-ASCT remained poor until the availability of CAR-T cell treatment. To appreciate this development, understanding the outcome of these patients in the pre-CAR-T era is essential. METHODS We retrospectively analyzed 125 consecutive DLBCL patients who underwent HDCT/ASCT. RESULTS After a median follow-up of 26 months, OS and PFS were 65% and 55%. Fifty-three patients (42%) had a relapse (32 patients, 60%) or refractory disease (21 patients, 40%) after a median of 3 months post-ASCT. 81% of relapses occurred within the first year post-ASCT with an OS of 19% versus 40% at the last follow-up in patients with later relapses (p=0.0022). Patients with r/r disease after ASCT had inferior OS compared to patients in ongoing remission (23% versus 96%; p<0.0001). Patients relapsing post-ASCT without salvage therapy (n=22) had worse OS than patients with 1-4 subsequent treatment lines (n=31) (OS 0% versus 39%; median OS 3 versus 25 months; p<0.0001). Forty-one (77%) of patients relapsing after ASCT died, 35 of which due to progression. CONCLUSIONS Additional therapies can extend OS but mostly cannot prevent death in DLBCL relapsing/refractory post-ASCT. This study may serve as a reference to emerging results after CAR-T treatment in this population

Fabrication and Testing of Large Flats

ABSTRACT Flat mirrors of around 1 meter are efficiently manufactured with large plano polishers and measured with Fizeau interferometry. We have developed technologies and hardware that allow fabrication and testing of flat mirrors that are much larger. The grinding and polishing of the large surfaces uses conventional laps driven under computer control for accurate and systematic control of the surface figure. The measurements are provided by a combination of a scanning pentaprism test, capable of measuring power and low order irregularity over diameters up to 8 meters, and subaperture Fizeau interferometry. We have developed a vibration insensitive Fizeau interferometer with 1 meter aperture and software to optimally combine the data from the subaperture tests. These methods were proven on a 1.6 m flat mirror that was finished to 6 nm rms irregularity and 11 nm rms power

Differential glycosylation of envelope gp120 is associated with differential recognition of HIV-1 by virus-specific antibodies and cell infection

Background: HIV-1 entry into host cells is mediated by interactions between the virus envelope glycoprotein (gp120/gp41) and host-cell receptors. N-glycans represent approximately 50% of the molecular mass of gp120 and serve as potential antigenic determinants and/or as a shield against immune recognition. We previously reported that N-glycosylation of recombinant gp120 varied, depending on the producer cells, and the glycosylation variability affected gp120 recognition by serum antibodies from persons infected with HIV-1 subtype B. However, the impact of gp120 differential glycosylation on recognition by broadly neutralizing monoclonal antibodies or by polyclonal antibodies of individuals infected with other HIV-1 subtypes is unknown. Methods: Recombinant multimerizing gp120 antigens were expressed in different cells, HEK 293T, T-cell, rhabdomyosarcoma, hepatocellular carcinoma, and Chinese hamster ovary cell lines. Binding of broadly neutralizing monoclonal antibodies and polyclonal antibodies from sera of subtype A/C HIV-1-infected subjects with individual gp120 glycoforms was assessed by ELISA. In addition, immunodetection was performed using Western and dot blot assays. Recombinant gp120 glycoforms were tested for inhibition of infection of reporter cells by SF162 and YU.2 Env-pseudotyped R5 viruses. Results: We demonstrated, using ELISA, that gp120 glycans sterically adjacent to the V3 loop only moderately contribute to differential recognition of a short apex motif GPGRA and GPGR by monoclonal antibodies F425 B4e8 and 447-52D, respectively. The binding of antibodies recognizing longer peptide motifs overlapping with GPGR epitope (268 D4, 257 D4, 19b) was significantly altered. Recognition of gp120 glycoforms by monoclonal antibodies specific for other than V3-loop epitopes was significantly affected by cell types used for gp120 expression. These epitopes included CD4-binding site (VRC03, VRC01, b12), discontinuous epitope involving V1/V2 loop with the associated glycans (PG9, PG16), and an epitope including V3-base-, N332 oligomannose-, and surrounding glycans-containing epitope (PGT 121). Moreover, the different gp120 glycoforms variably inhibited HIV-1 infection of reporter cells. Conclusion: Our data support the hypothesis that the glycosylation machinery of different cells shapes gp120 glycosylation and, consequently, impacts envelope recognition by specific antibodies as well as the interaction of HIV-1 gp120 with cellular receptors. These findings underscore the importance of selection of appropriately glycosylated HIV-1 envelope as a vaccine antigen

Season of Prescribed Fire Determines Grassland Restoration Outcomes After Fire Exclusion and Overgrazing

Fire exclusion and mismanaged grazing are globally important drivers of environmental change in mesic C4 grasslands and savannas. Although interest is growing in prescribed fire for grassland restoration, we have little long-term experimental evidence of the influence of burn season on the recovery of herbaceous plant communities, encroachment by trees and shrubs, and invasion by exotic grasses. We conducted a prescribed fire experiment (seven burns between 2001 and 2019) in historically fire-excluded and overgrazed grasslands of central Texas. Sites were assigned to one of four experimental treatments: summer burns (warm season, lightning season), fall burns (early cool season), winter burns (late cool season), or unburned (fire exclusion). To assess restoration outcomes of the experiment, in 2019, we identified old-growth grasslands to serve as reference sites. Herbaceous-layer plant communities in all experimental sites were compositionally and functionally distinct from old-growth grasslands, with little recovery of perennial C4 grasses and long-lived forbs. Unburned sites were characterized by several species of tree, shrub, and vine; summer sites were characterized by certain C3 grasses and forbs; and fall and winter sites were intermediate in composition to the unburned and summer sites. Despite compositional differences, all treatments had comparable plot-level plant species richness (range 89–95 species/1000 m2). At the local-scale, summer sites (23 species/m2) and old-growth grasslands (20 species/m2) supported greater richness than unburned sites (15 species/m2), but did not differ significantly from fall or winter sites. Among fire treatments, summer and winter burns most consistently produced the vegetation structure of old-growth grasslands (e.g., mean woody canopy cover of 9%). But whereas winter burns promoted the invasive grass Bothriochloa ischaemum by maintaining areas with low canopy cover, summer burns simultaneously limited woody encroachment and controlled B. ischaemum invasion. Our results support a growing body of literature that shows that prescribed fire alone, without the introduction of plant propagules, cannot necessarily restore old-growth grassland community composition. Nonetheless, this long-term experiment demonstrates that prescribed burns implemented in the summer can benefit restoration by preventing woody encroachment while also controlling an invasive grass. We suggest that fire season deserves greater attention in grassland restoration planning and ecological research

Systemic and Lower Respiratory Tract Immunity to SARS-CoV-2 Omicron and Variants in Pediatric Severe COVID-19 and Mis-C

Mucosal immunity plays an important role in the control of viral respiratory infections like SARS-CoV-2. While systemic immune responses against the SARS-2-CoV-2 have been studied in children, there is no information on mucosal antibody response, especially in the lower respiratory tract of children coronavirus disease 2019 (COVID-19) and post-infectious multisystem inflammatory syndrome in children (MIS-C) against emerging SARS-CoV-2 variants. Therefore, we evaluated neutralizing antibody responses in paired plasma and endotracheal aspirates of pediatric severe, acute COVID-19 or MIS-C patients against SARS-CoV-2 WA1/2020, as well as against variants of concern (VOCs). Neutralizing antibody responses against the SARS-CoV-2 WA1/2020 strain in pediatric plasma were 2-fold or 35-fold higher compared with the matched endotracheal aspirate in COVID-19 or MIS-C patients, respectively. In contrast to plasma, neutralizing antibody responses against the VOCs and variants of interest (VOIs) in endotracheal aspirates were lower, with only one endotracheal aspirate demonstrating neutralizing titers against the Iota, Kappa, Beta, Gamma, and Omicron variants. In conclusion, our findings suggest that children and adolescents with severe COVID-19 or MIS-C have weak mucosal neutralizing antibodies in the trachea against circulating SARS-CoV-2 Omicron and other VOCs, which may have implications for recovery and for re-infection with emerging SARS-CoV-2 variants

Law professors want hearing, vote on Garland

Dear Senator Fischer and Senator Sasse, We write this as citizens, but we all teach at the University of Nebraska College of Law. We hold different political viewpoints and disagree frequentIy with each other on political and legal issues. As law professors, however, we share a deep commitment to the rule of law and an impartial judiciary. We therefore urge you to hold confirmation hearings and a vote on President Obama\u27s Supreme Court nominee, Chief Judge Merrick B. Garland

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

Insights on the Dusty Torus and Neutral Torus From Optical and X-Ray Obscuration in A Complete Volume Limited Hard X-Ray Agn Sample

We describe a complete volume limited sample of nearby active galaxies selected by their 14–195 keV luminosity, and outline its rationale for studying the mechanisms regulating gas inflow and outflow. We also describe a complementary sample of inactive galaxies, selected to match the host galaxy properties. The active sample appears to have no bias in terms of active galactic nucleus (AGN) type, the only difference being the neutral absorbing column, which is two orders of magnitude greater for the Seyfert 2s. In the luminosity range spanned by the sample, ${\rm log} {{L}_{14-195\,{\rm keV}}}[{\rm erg}\;{{{\rm s}}^{-1}}]=42.4$–43.7, the optically obscured and X-ray absorbed fractions are 50%–65%. The similarity of these fractions to more distant spectroscopic AGN samples, although over a limited luminosity range, suggests that the torus does not strongly evolve with redshift. Our sample confirms that X-ray unabsorbed Seyfert 2s are rare, comprising not more than a few percent of the Seyfert 2 population. At higher luminosities, the optically obscured fraction decreases (as expected for the increasing dust sublimation radius), but the X-ray absorbed fraction changes little. We argue that the cold X-ray absorption in these Seyfert 1s can be accounted for by neutral gas in clouds that also contribute to the broad-line region (BLR) emission, and suggest that a geometrically thick neutral gas torus co-exists with the BLR and bridges the gap to the dusty torus

Don\u27t Reinvent the Wheel: Legal Research Guides and Bibliographies Will Save You Valuable Time and Effort

When researching unfamiliar areas of law it is often helpful to consult research guides and bibliographies. These resources can expedite the research process by identifying, compiling, and explaining the various tools needed to successfully research a legal topic. Research guides and bibliographies can be found in a number of online and print sources. By using a variety of specialized tools, one can quickly locate quality legal research guides and bibliographies no matter where they are

Legal Research in the Digital Age: Authentication and Preservation of Primary Material

Most legal professionals have used free online resources to help in the legal research process. Whether it is an opinion downloaded from a court\u27s Web site, a federal statute located using Cornell\u27s Legal Information Institute (LII), an article on Wikipedia, or a post on someone\u27s blawg, the quantity and variety of free online resources seems to grow on a daily basis. Some have even wondered if these resources can one day replace the need to subscribe to a computer-assisted legal research (CALR) service such as Westlaw or LexisNexis. Late last year, the blogosphere was abuzz with this question after Google added legal journals and opinions to its Google Scholar search tool. Although members of the legal community already use the Web as a complement to fee-based CALR services, the role free Web resources play in the research process will likely expand. This article will examine the appropriate short-term and long-term roles free Web resources should play in the legal research process. Particular attention will be focused on the authentication and preservation of online primary legal material