m6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade

Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N6-methyladenosine (m6A) mRNA demethylation by fat mass and obesity-associated protein (FTO) increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy. FTO level is increased in human melanoma and enhances melanoma tumorigenesis in mice. FTO is induced by metabolic starvation stress through the autophagy and NF-κB pathway. Knockdown of FTO increases m6A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m6A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFNγ) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity. Our findings demonstrate a crucial role of FTO as an m6A demethylase in promoting melanoma tumorigenesis and anti-PD-1 resistance, and suggest that the combination of FTO inhibition with anti-PD-1 blockade may reduce the resistance to immunotherapy in melanoma. © 2019, The Author(s)

Mid-Infrared Images of Luminous Infrared Galaxies in a Merging Sequence

We report mid-infrared observations of several luminous infrared galaxies (LIGs) carried out with the Infrared Space Observatory. Our sample was chosen to represent different phases of a merger sequence of galaxy-galaxy interaction with special emphasis on early/intermediate stages of merging. The mid-infrared emission of these LIGs shows extended structures for the early and intermediate mergers, indicating that most of the mid-infrared luminosities are not from a central active galactic nucleus (AGN). Both the infrared hardness (indicated by the IRAS 12, 25, and 60 \micron flux density ratios) and the peak-to-total flux density ratios of these LIGs increase as projected separation of these interacting galaxies become smaller, consistent with increasing star formation activities that are concentrated to a smaller area as the merging process advances. These observations provide among the first observational constraint of largely theoretically based scenarios.Comment: 10 pages, 3 figures, please refer to ApJ Letters for the final versio

Delivering steady-state product quality with an intensified and integrated perfusion cell culture process

Continuous biomanufacturing provides many important strategic advantages for the production of protein therapeutics through process integration, simplification and intensification. To achieve upstream process intensification, Sanofi is currently developing robust cell culture processes that can achieve ultra-high cell densities and productivities (“push to high”) while minimizing cell-specific perfusion rates (“push to low”). We have applied ATF perfusion technology and improved the cell culture environment to achieve high cell densities and volumetric productivities with minimal ATF filter fouling. Meanwhile, we have employed high-throughput screening strategies to increase medium depth and reduce medium requirements. We will describe results as well as ongoing efforts to further intensify this continuous cell culture platform and realize even more of its significant upward potential. Continuous biomanufacturing also has the potential to deliver robust, steady-state product quality, resulting in enormous operational flexibility. Instead of traditionally defining batches by unit operation, product can be batched in time (first-in, first-out), removing downstream processing constraints and minimizing production cycle times. In this presentation, we use both theoretical models and experimental data to evaluate the effects of perfusion on product quality, considering the impact of perfusion-specific controllable parameters (e.g., perfusion rate, bleed rate, target viable cell density) on product quality. We also compare and contrast product quality attributes between perfusion and fed-batch processes and examine the feasibility of maintaining a process and product quality at steady state while presenting relevant, real-world case studies

Impact of Timing to initiate adjuvant therapy On Survival of Elderly Glioblastoma Patients Using the Seer-Medicare and National Cancer Databases

The optimal time to initiate adjuvant therapy (AT) in elderly patients with glioblastoma (GBM) remains unclear. We investigated the impact of timing to start AT on overall survival (OS) using two national-scale datasets covering elderly GBM populations in the United States. A total of 3159 and 8161 eligible elderly GBM patients were derived from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked dataset (2004-2013) and the National Cancer Database (NCDB) (2004-2014), respectively. The intervals in days from the diagnosis to the initiation of AT were categorized based on two scenarios: Scenario I (quartiles), ≤ 15, 16-26, 27-37, and ≥ 38 days; Scenario II (median), \u3c 27, and ≥ 27 days. The primary outcome was OS. We performed the Kaplan-Meier and Cox proportional hazards regression methods for survival analysis. A sensitivity analysis was performed using Propensity Score Matching (PSM) method to achieve well-balanced characteristics between early-timing and delayed-timing in Scenario II. Improved OS was observed among patients who underwent resection and initiated AT with either a modest delay (27-37 days) or a longer delay (≥ 38 days) compared to those who received AT immediately (≤ 15 days) from both the SEER-Medicare dataset [adjusted hazard ratio (aHR) 0.74, 95% CI 0.64-0.84, P \u3c 0.001; and aHR 0.81, 95% CI 0.71-0.92, P = 0.002] and the NCDB (aHR 0.83, 95% CI 0.74-0.93, P = 0.001; and aHR 0.87, 95% CI 0.77-0.98, P = 0.017). The survival advantage is observed in delayed-timing group as well in Scenario II. For elderly patients who had biopsy only, improved OS was only detected in a longer delay (Scenario I: ≥ 38 days vs. ≤ 15 days) or the delayed-timing group (Scenario II: ≥ 27 days vs. \u3c 27 days) in the NCDB while no survival difference was seen in SEER-Medicare population. For the best timing to start AT in elderly GBM patients, superior survivals were observed among those who had craniotomy and initiated AT with a modest (27-37 days) or longer delays (≥ 38 days) following diagnosis using both the SEER-Medicare and NCDB datasets (Scenario I). Such survival advantage was confirmed when categorizing delayed-timing vs. early-timing with the cut-off at 27 day in both datasets (Scenario II). The increased likelihood of receiving delayed AT (≥ 27 days) was significantly associated with tumor resection (STR/GTR), years of diagnosis after 2006, African American and Hispanics races, treatments at academic facilities, and being referred. There is no difference in timing of AT on survival among elderly GBM patients who had biopsy in the SEER-Medicare dataset. In conclusion, initiating AT with a modest delay (27-37 days) or a longer delay (≥ 38 days) after craniotomy may be the preferred timing in the elderly GBM population

On-chip optical diode based on silicon photonic crystal heterojunctions

Optical isolation is a long pursued object with fundamental difficulty in integrated photonics. As a step towards this goal, we demonstrate the design, fabrication, and characterization of on-chip wavelength-scale optical diodes that are made from the heterojunction between two different silicon two-dimensional square-lattice photonic crystal slabs with directional bandgap mismatch and different mode transitions. The measured transmission spectra show considerable unidirectional transmission behavior, in good agreement with numerical simulations. The experimental realization of on-chip optical diodes using all-dielectric, passive, and linear silicon photonic crystal structures may help to construct on-chip optical logical devices without nonlinearity or magnetism, and would open up a road towards photonic computers.Comment: 14 pages, 5 figure

Overcoming process intensification challenges to deliver a manufacturable and competitive integrated continuous biomanufacturing platform

Groups in both industry and academia have achieved high densities and productivities in perfusion cell culture processes. At Sanofi, we have demonstrated perfusion densities greater than 100 million cells/mL (with associated high productivities) at a cell-specific perfusion rate of only 20 pL/cell/day. This process intensification reduces the footprint of upstream unit operations as well as capital and operating expenses of manufacturing facilities. The continuous nature of perfusion cell culture also creates opportunities for integration of continuous downstream operations, leading to further process intensifications and volume reductions. In this presentation, we will discuss our work on several upstream challenges that must be overcome to create a manufacturable, continuous bioprocessing platform. These will include (1) mitigation strategies for the large shear forces accompanying the high sparge rates necessary to sustain a high-density culture, (2) efforts to minimize the economic and logistical burden of media cost and consumption in perfusion cell culture, (3) the challenge of maintaining consistent product quality over long durations and (4) scale-up of these intensified processes to 50-L and 500-L manufacturing-scale systems. We can address each of these areas to create an efficient, competitive cell culture platform that generates high cell viabilities and excellent product quality at manufacturing scales. We will demonstrate real-world examples of both enzyme and antibody-producing processes, showing that such a platform can reliably deliver good results across diverse products

Ample Pairs

We show that the ample degree of a stable theory with trivial forking is preserved when we consider the corresponding theory of belles paires, if it exists. This result also applies to the theory of $H$-structures of a trivial theory of rank $1$.Comment: Research partially supported by the program MTM2014-59178-P. The second author conducted research with support of the programme ANR-13-BS01-0006 Valcomo. The third author would like to thank the European Research Council grant 33882