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Primary results (median follow-up, 10.7 months) from the pivotal EPCORE®NHL-1 study in relapsed or refractory (R/R) large B-cell lymphoma (LBCL) demonstrated deep, durable responses with epcoritamab, a CD3xCD20 bispecific antibody, when used as monotherapy. We report long-term efficacy and safety results in patients with LBCL (N= 157; 25.1-month median follow-up). As of April 21, 2023, overall response rate was 63.1% and complete response (CR) rate was 40.1%. Estimated 24-month progression-free survival (PFS) and overall survival (OS) rates were 27.8% and 44.6%, respectively. An estimated 64.2% of complete responders remained in CR at 24 months. Estimated 24-month PFS and OS rates among complete responders were 65.1% and 78.2%, respectively. Of 119 minimal residual disease (MRD)-evaluable patients, 45.4% had MRD negativity, which correlated with longer PFS and OS. CR rates were generally consistent across predefined subgroups: 36% prior chimeric antigen receptor (CAR) T-cell therapy, 32% primary refractory disease, and 37% International Prognostic Index ≥3. The most common treatment-emergent adverse events were cytokine release syndrome (51.0%), pyrexia (24.8%), fatigue (24.2%), and neutropenia (23.6%). These results underscore the long-term benefit of epcoritamab for treating R/R LBCL with deep responses across subgroups, including patients with hard-to-treat disease and expected poor prognosis (ClinicalTrials.gov Registration: NCT03625037).

Simulation models of watershed hydrology (also referred to as "rainfall-runoff models") are calibrated to the best available streamflow data, which are typically published discharge time series at the outlet of the watershed. Even after calibration, the model generally cannot replicate the published discharges because of simplifications of the physical system embedded in the model structure and uncertainties of the input data and of the estimated model parameters, which, although optimized for the given calibration data, remain uncertain. The input data errors are caused by uncertainties in the forcing data, such as precipitation and other climatological data, and in the published discharges used for calibration. In the numerical algorithms used for calibration, the published discharges are often assumed to be without error, but they are themselves uncertain, typically having been computed using ratings, which are models fitted to uncertain discharge measurements. In this study, uncertainty of published daily discharge data and how the discharge uncertainty is transmitted to the parameter values of the Hydrological Simulation Program-FORTRAN (HSPF) rainfall-runoff model and to the simulated discharge at both calibration and prediction locations were investigated for the Lake Michigan diversion in northeastern Illinois and northwestern Indiana. The HSPF model used in this study is used by the U.S. Army Corps of Engineers as part of quantifying the diversion of water from Lake Michigan by the State of Illinois. In this study, the model is calibrated jointly at two watersheds in the study area; the resulting model is considered the base model in this study. Seven other gaged watersheds in the study area are used for testing predictive simulations. A Bayesian rating curve estimation (BaRatin) approach, the BaRatin stage-period-discharge (SPD) method, was used to estimate the uncertainty of the published discharge from the calibration watersheds. To characterize the effect of the discharge uncertainty on parameter values, the HSPF model parameters were recalibrated to 17 nonrandomly selected pairs of discharge series from the BaRatin SPD analysis. To provide an indicator of the effect of parameter uncertainty to compare to the effect of discharge uncertainty, 1,000 parameter sets also were randomly generated from the estimated parameter covariance matrix of the base model. The recalibrated and random parameter sets were then used in HSPF simulations of discharge at the two calibration watersheds and at the seven prediction watersheds. Selected discharge summary statistics--the period-of-study (POS, water years 1997 to 2015) mean discharge, selected flow-duration curve (FDC) quantiles, and water year mean discharges--are used to characterize the variability between simulated and published discharge. A normalized variability index (VN) is used as a measure of the uncertainty of flow statistics arising from the uncertainty of the sources considered in this study. When this index is at least 1, the variability of the simulations is large enough to explain the median error between simulated and published values, although offsetting errors from other sources are also likely. When the index is appreciably less than 1, the variability of the simulations is clearly insufficient to explain the median error between simulated and published values. At the two calibration watersheds and for results of the two simulation sets considered together, the VN values ranged from 0.2 to 0.8 for POS mean discharge, from 0.3 to 0.6 in the median for a set of FDC quantiles, and from 0.1 to 0.2 in the median for water year mean discharges. These values indicate that substantial uncertainty remains unexplained. Even though two watersheds were used in calibration, that calibration was highly constrained because it was applied to the watersheds simultaneously and was subject to parameter regularization that constrained the adjustment of the parameters from their initial values. These constraints were applied to avoid overfitting to the calibration watersheds and thus to increase the likelihood that the resulting parameters would give accurate results at watersheds not used in the calibration, but they created a parameter transfer error in the calibration watershed results shown by the balancing of errors between the two watersheds. Additional remaining error sources include model structural error and meteorological forcing error to the degree that the calibration was unable to adjust the parameters to account for these errors. At the prediction watersheds, the corresponding VN values were almost always substantially lower than those values at the calibration watersheds. This result is expected because the prediction watersheds have additional uncertainty, including parameter transfer error. The work described in this report provides preliminary estimates of a limited range of sources of error in predicted discharge uncertainty. Future work would be beneficial to obtain a better statistical characterization of the effect of the uncertainty of calibration discharge series and to address additional sources of uncertainty, such as from precipitation input data used in calibration and prediction and from structural (model) errors. [ABSTRACT FROM AUTHOR]

Shear stress growth and relaxation behavior of two well-characterized SBS block copolymers have been studied using a Melt Elasticity Tester. Effects of casting solvents on the transient rheological properties and structure variation during flow are determined via samples cast from THF/MEK and cyclohexane. The temperature dependence of the observed shear stress at the yield point and steady-state viscosities provides insight into the mechanism of structure breakdown induced by the applied flow. Shear stress relaxation upon cessation of flow reveals complex behavior, depending on temperature, casting solvents, and duration of previous flow. Strain recovery data have also been obtained, indicating strong dependence on the composition of the copolymers. Significance of these observations in terms of the melt structure of SBS is discussed.

A viscosity constitutive equation has been developed to describe PMMA - MMA solutions over a wide range of concentration and temperature. The approach used here combines both free-volume and coil-coil interaction considerations. The final expression successfully correlates not only our experimental data on several solutions but also literature melt data. This equation provides an essential step in modeling tubular polymerization reactors, where the residence time distribution depends strongly on the velocity profile development in the tube, and thus the rheological properties of the reacting PMMA - MMA mixture at different conversion levels and temperatures.

Advances in Acute Myeloid Leukemia (AML) research have shown that the bone marrow microenvironment may distinctly vary across disease subtypes, and that this variation is associated with disease risk and response to conventional therapies. Novel therapies aimed at altering the tumor microenvironment, such as T-cell redirection, CAR-T and checkpoint inhibition, are emerging as promising treatment options for AML patients; however, there remains a critical need to determine how response to immune modulation may vary within different subsets of AML. Thus, in collaboration with the Beat AML Consortium, we carried out comprehensive mass cytometry profiling of patient bone marrow samples of nearly 100 Beat AML subjects and characterized their ex vivoresponse to several immune modulators.

Background:Immunoglobulin (IGH, IGL, IGK) and non-immunoglobulin (PVT1, TXNDC5, FAM46C, DUSP22, etc.) enhancers hijacking by variable genes (MYC, MAF, MAFB, CCND1/2/3, MMSET, IRF4) is a recognized oncogenic driver event in MM. However, the identity of the transcription factors (TFs) or transcriptional regulatory complexes binding and regulating the activity of these enhancers remains to be fully elucidated and may yield valuable therapeutic targets. As such the discovery of the BET family member BRD4 as the master histone acetyl mark reader at enhancers loci regulating MYC lead to promising therapeutic developments in MM and numerous other cancers. Immunomodulatory drugs (IMiDs) promote the proteasomal degradation of IKAROS (IKZF1) and AIOLOs (IKZF3) leading to the transcriptional repression of MYC and the suppression of MM cells survival and proliferation. However, acquired resistance to IMIDs and the loss of the transcriptional repression of MYC are nearly universal and occur in spite of sustained IKZF1/3 degradation suggesting that transcriptional rewiring may be sustaining hijacked enhancers activity and transcription of driver oncogenes.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.