Integrated continuous bioprocessing: Costs of goods versus cost of development

A significant benefit of continuous manufacture is the potential to provide higher productivities compared to traditional batch processes. Smaller facilities with single-use technology could become preferable offering reductions in the capital expenditure. Hence, continuous bioprocessing could offer savings in the cost of goods (COG). However there are other cost factors that need to be considered when evaluating bioprocess facilities in addition to the COG. The cost of development (COD) is a key cost driver that could affect the decision to adopt new manufacturing methods. This study aims to carry out a holistic financial assessment of introducing continuous bioprocessing strategies by considering both the COG and the COD. To be able to perform this level of analysis a decisional tool was developed at University College London to evaluate the cost of implementing traditional batch or continuous bioprocessing (end-to-end and hybrid) at various stages of the drug development pathway. A range of scenarios investigated the economics of different manufacturing strategies at various demands, company sizes and stages of manufacture (pre-clinical, clinical and commercial). Therefore, through the analysis it was possible to determine whether the apparent benefits of continuous bioprocessing translate into cost savings, focusing on the development and commercialisation of monoclonal antibodies

Nitrogen Fertilizer Suppresses Mineralization of Soil Organic Matter in Maize Agroecosystems

The possibility that N fertilizer increases soil organic matter (SOM) mineralization and, as a result, reduces SOM stocks has led to a great debate about the long-term sustainability of maize-based agroecosystems as well as the best method to estimate fertilizer N use efficiency (FNUE). Much of this debate is because synthetic N fertilizer can positively or negatively affect SOM mineralization via several direct and indirect pathways. Here, we test a series of hypotheses to determine the direction, magnitude, and mechanism of N fertilizer effect on SOM mineralization and discuss the implications for methods to estimate FNUE. We measured the effect of synthetic N fertilizer on SOM mineralization via gross ammonification at two long-term experiments in central and southern Iowa, USA with replicated plots of continuous maize that received one of three “historical” N fertilizer rates (zero, moderate or high) from 1999 to 2014. In 2015, prior to our measurements, we split the historical N fertilizer rate plots into two subplots that received either the site-specific agronomic optimum N rate or zero N fertilizer. At the onset of rapid maize N uptake, N fertilizer reduced gross ammonification by 13–21% (2–5 kg NH4-N ha−1 d−1). A companion laboratory experiment rejected the hypothesis that differences in net primary productivity between fertilized and unfertilized treatments explained the negative effect of N fertilizer on SOM mineralization. Moreover, the NH4+ pool size was negatively correlated with the gross ammonification rate (r2 = 0.85, p \u3c 0.001). Thus, we conclude that NH4+ -N fertilizer had a direct suppressive effect on SOM mineralization. These results demonstrate that the direct effect of N fertilizer on microbial activity can exceed the indirect effects of N fertilizer via large changes in NPP that alter organic matter inputs, soil temperature and moisture content. The magnitude of this effect and specificity to NH4+ -N has significant implications for fertilizer management as well as the measurement and modeling of agroecosystem N dynamics including FNUE

Nitrogen Fertilizer Suppresses Mineralization of Soil Organic Matter in Maize Agroecosystems

The possibility that N fertilizer increases soil organic matter (SOM) mineralization and, as a result, reduces SOM stocks has led to a great debate about the long-term sustainability of maize-based agroecosystems as well as the best method to estimate fertilizer N use efficiency (FNUE). Much of this debate is because synthetic N fertilizer can positively or negatively affect SOM mineralization via several direct and indirect pathways. Here, we test a series of hypotheses to determine the direction, magnitude, and mechanism of N fertilizer effect on SOM mineralization and discuss the implications for methods to estimate FNUE. We measured the effect of synthetic N fertilizer on SOM mineralization via gross ammonification at two long-term experiments in central and southern Iowa, USA with replicated plots of continuous maize that received one of three “historical” N fertilizer rates (zero, moderate or high) from 1999 to 2014. In 2015, prior to our measurements, we split the historical N fertilizer rate plots into two subplots that received either the site-specific agronomic optimum N rate or zero N fertilizer. At the onset of rapid maize N uptake, N fertilizer reduced gross ammonification by 13–21% (2–5 kg NH4-N ha−1 d−1). A companion laboratory experiment rejected the hypothesis that differences in net primary productivity between fertilized and unfertilized treatments explained the negative effect of N fertilizer on SOM mineralization. Moreover, the NH4+ pool size was negatively correlated with the gross ammonification rate (r2 = 0.85, p < 0.001). Thus, we conclude that NH4+-N fertilizer had a direct suppressive effect on SOM mineralization. These results demonstrate that the direct effect of N fertilizer on microbial activity can exceed the indirect effects of N fertilizer via large changes in NPP that alter organic matter inputs, soil temperature and moisture content. The magnitude of this effect and specificity to NH4+-N has significant implications for fertilizer management as well as the measurement and modeling of agroecosystem N dynamics including FNUE

Nitrogen Fertilizer Suppresses Mineralization of Soil Organic Matter in Maize Agroecosystems

The possibility that N fertilizer increases soil organic matter (SOM) mineralization and, as a result, reduces SOM stocks has led to a great debate about the long-term sustainability of maize-based agroecosystems as well as the best method to estimate fertilizer N use efficiency (FNUE). Much of this debate is because synthetic N fertilizer can positively or negatively affect SOM mineralization via several direct and indirect pathways. Here, we test a series of hypotheses to determine the direction, magnitude, and mechanism of N fertilizer effect on SOM mineralization and discuss the implications for methods to estimate FNUE.Wemeasured the effect of synthetic N fertilizer on SOMmineralization via gross ammonification at two long-term experiments in central and southern Iowa, USA with replicated plots of continuous maize that received one of three “historical” N fertilizer rates (zero, moderate or high) from 1999 to 2014. In 2015, prior to our measurements, we split the historical N fertilizer rate plots into two subplots that received either the site-specific agronomic optimum N rate or zero N fertilizer. At the onset of rapid maize N uptake, N fertilizer reduced gross ammonification by 13–21% (2–5 kg NH4-N ha−1 d−1). A companion laboratory experiment rejected the hypothesis that differences in net primary productivity between fertilized and unfertilized treatments explained the negative effect of N fertilizer on SOM mineralization. Moreover, the NH+ 4 pool size was negatively correlated with the gross ammonification rate (r2 = 0.85, p This article is published as Mahal, Navreet Kaur, William R. Osterholz, Fernando E. Miguez, Hanna Poffenbarger, John E. Sawyer, Daniel C. Olk, Sotirios Archontoulis, and Michael J. Castellano. "Nitrogen fertilizer suppresses mineralization of soil organic matter in maize agroecosystems." Frontiers in Ecology and Evolution 7 (2019): 59. doi: 10.3389/fevo.2019.00059.</p

Molecular, immunologic, and clinicodemographic landscape of MYC-amplified (MYCamp) advanced prostate cancer (PCa)

5041 Background: The MYC oncogene is one of the most commonly amplified genes in PCa, contributes to androgen independent growth, and is potentially targetable. We sought to define the molecular, immunologic, and clinicodemographic landscape of MYCamp in advanced PCa to better understand progression and establish rationale for personalized treatments and combinations. Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on tumor samples from predominantly advanced PCa samples. MYCamp was defined as copy number (CN) ≥6. PD-L1 IHC was performed using Dako 22C3. A subset of patients (pts) with advanced PCa were selected from the Flatiron Health- Foundation Medicine (FM) clinicogenomic database (CGDB), a nationwide de-identified EHR-derived clinical DB linked to FM CGP data for pts treated from 01/2011-12/2020. The de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). Results: The genomic profiles of 12,528 tissue samples from unique PCa pts (including hormone sensitive and castrate resistant) were evaluated. MYCamp was detected in 10.6%, with a median MYC CN of 8. Median age was 67 years (67 for MYCwt versus 68 for MYCamp). MYCamp occurred at a higher frequency in men with African (N = 190/1,473, 12.9%) versus European (N = 996/9,796, 10.2%) ancestry (P = 0.002), was more frequent in metastatic biopsy sites vs primary (15.7% vs 6.2%, P 15 was enriched for PD-L1 positivity (26.1%) compared with MYCwt (9.8%) or MYCamp CN 6-15 (11.5%) (CN > 15 vs wt P = 0.025). In pts with MYCamp vs MYCwt PCa AR, RAD21, PTEN, CCND1, ZNF703, FGF19, FGFR1, and FGF3 each had significantly higher rates of CN changes (all p 0) from PCa pts MYCamp was detected in 2.0% (28/1,402), and in 4.5% (20/445) with cTF > 20%. Among evaluable PCa pts in the CGDB, (67 MYCamp and 658 MYCwt) MYCamp did not significantly impact treatment decisions, with the majority receiving novel hormone therapies (35.8% MYCamp vs. 31.5% MYCwt) or chemotherapy containing regimens (37.3% MYCamp vs. 27.7% MYCwt) as first therapy after CGP report. Conclusions: Herein, we report the largest analysis to date of molecular, immunologic, and clinicodemographic features of MYCamp advanced PCa. These findings suggest that MYCamp defines a biologically distinct subset of PCa pts for whom personalized combination treatments utilizing targeted and/or immunotherapies may be effective. Independent cohorts are needed to validate these findings

The N-glycome regulates the endothelial-to-hematopoietic transition

Definitive hematopoietic stem and progenitor cells (HSPCs) arise from the transdifferentiation of hemogenic endothelial cells (hemECs). The mechanisms of this endothelial-to-hematopoietic transition (EHT) are poorly understood. We show that microRNA-223 (miR-223)-mediated regulation of N-glycan biosynthesis in endothelial cells (ECs) regulates EHT. miR-223 is enriched in hemECs and in oligopotent nascent HSPCs. miR-223 restricts the EHT of lymphoid-myeloid lineages by suppressing the mannosyltransferase alg2 and sialyltransferase st3gal2, two enzymes involved in protein N-glycosylation. ECs that lack miR-223 showed a decrease of high mannose versus sialylated sugars on N-glycoproteins such as the metalloprotease Adam10. EC-specific expression of an N-glycan Adam10 mutant or of the N-glycoenzymes phenocopied miR-223 mutant defects. Thus, the N-glycome is an intrinsic regulator of EHT, serving as a key determinant of the hematopoietic fate