Challenges and their resolutions during process development and tech transfer of a late stage bispecific antibody product

During the Phase III process development and tech transfer of a bispecific antibody project in Sanofi, many technical and logistical challenges were encountered for this cross-site collaboration project. In particular, Phase III process development and tech transfer involves three different sites as sending and receiving units located in different continents using different scales of equipment. Due to this constraint, additional considerations are required to address gaps between different small scale models prior to scale-up in order to de-risk the challenges that we may encounter during process transfer. Particularly, computational fluid dynamics (CFD) modeling and first principles calculation are used not only to support scale-up but also to bridge the difference between the small-scale models. In addition to this logistical challenge, the team also systematically addressed some technical challenges in order to close several major manufacturability gaps between the Phase I/II and the Phase III processes. This poster summarizes our approach to resolve each of these challenges in order to collaboratively accomplish a successful tech transfer

Indirect Probes of the MSSM after the Higgs Discovery

We study the minimal supersymmetric standard model (MSSM) with minimal flavor violation (MFV), imposing constraints from flavor physics observables and MSSM Higgs searches, in light of the recent discovery of a 125 GeV Higgs boson by ATLAS and CMS. We analyze the electroweak vacuum stability conditions to further restrict the MSSM parameter space. In addition, a connection to ultraviolet physics is shown via an implementation of renormalization group running, which determines the TeV-scale spectrum from a small set of minimal supergravity parameters. Finally, we investigate the impact from dark matter direct detection searches. Our work highlights the complementarity of collider, flavor and dark matter probes in exploring the MSSM, and shows that even in a MFV framework, flavor observables constrain the MSSM parameter space well beyond the current reach of direct SUSY particle searches.Comment: 28 pages, 15 figures; v2, updated with new LHCb and direct A->tau tau results from HCP 2012, references adde

Self-supervised Interest Point Detection and Description for Fisheye and Perspective Images

Keypoint detection and matching is a fundamental task in many computer vision problems, from shape reconstruction, to structure from motion, to AR/VR applications and robotics. It is a well-studied problem with remarkable successes such as SIFT, and more recent deep learning approaches. While great robustness is exhibited by these techniques with respect to noise, illumination variation, and rigid motion transformations, less attention has been placed on image distortion sensitivity. In this work, we focus on the case when this is caused by the geometry of the cameras used for image acquisition, and consider the keypoint detection and matching problem between the hybrid scenario of a fisheye and a projective image. We build on a state-of-the-art approach and derive a self-supervised procedure that enables training an interest point detector and descriptor network. We also collected two new datasets for additional training and testing in this unexplored scenario, and we demonstrate that current approaches are suboptimal because they are designed to work in traditional projective conditions, while the proposed approach turns out to be the most effective.Comment: CVPR Workshop on Omnidirectional Computer Vision, 202

A neurodegenerative perspective on mitochondrial optic neuropathies

Mitochondrial optic neuropathies constitute an important cause of chronic visual morbidity and registrable blindness in both the paediatric and adult population. It is a genetically heterogeneous group of disorders caused by both mitochondrial DNA (mtDNA) mutations and a growing list of nuclear genetic defects that invariably affect a critical component of the mitochondrial machinery. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mtDNA disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene OPA1 that encodes for a mitochondrial inner membrane protein. The defining neuropathological feature is the preferential loss of retinal ganglion cells (RGCs) within the inner retina but, rather strikingly, the smaller calibre RGCs that constitute the papillomacular bundle are particularly vulnerable, whereas melanopsin-containing RGCs are relatively spared. Although the majority of patients with LHON and DOA will present with isolated optic nerve involvement, some individuals will also develop additional neurological complications pointing towards a greater vulnerability of the central nervous system (CNS) in susceptible mutation carriers. These so-called “plus” phenotypes are mechanistically important as they put the loss of RGCs within the broader perspective of neuronal loss and mitochondrial dysfunction, highlighting common pathways that could be modulated to halt progressive neurodegeneration in other related CNS disorders. The management of patients with mitochondrial optic neuropathies still remains largely supportive, but the development of effective disease-modifying treatments is now within tantalising reach helped by major advances in drug discovery and delivery, and targeted genetic manipulation

Higgs Signal for h to aa at Hadron Colliders

We assess the prospect of observing a neutral Higgs boson at hadron colliders in its decay to two spin-zero states, a, for a Higgs mass of 90-130 GeV, when produced in association with a W or Z boson. Such a decay is allowed in extensions of the MSSM with CP-violating interactions and in the NMSSM, and can dominate Higgs boson final states, thereby evading the LEP constraints on standard Higgs boson production. The light spin-zero state decays primarily via a to bb and tau+tau-, so this signal channel retains features distinct from the main backgrounds. Our study shows that at the Tevatron, there may be potential to observe a few events in the bb tau+tau- or bbbb channels with relatively small background, although this observation would be statistically limited. At the LHC, the background problem is more severe, but with cross sections and integrated luminosities orders of magnitude larger than at the Tevatron, the observation of a Higgs boson in this decay mode would be possible. The channel h to aa to bbbb would provide a large statistical significance, with a signal-to-background ratio on the order of 1:2. In these searches, the main challenge would be to retain the adequate tagging efficiency of b's and tau's in the low p_T region.Comment: Version to be published in JHEP. 20 pages, 5 figure

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

(R)-albuterol decreases immune responses: role of activated T cells

Racemic albuterol is an equimolar mixture of two isomers, (R) and (S). Whether (R) and (S) isomers and the combination of both exert different effects in immune activation is not well defined. We analyzed the effects of (R+S)-albuterol, (R)-albuterol and (S)-albuterol in a murine model of allergic pulmonary inflammation and in activated T cells. Mice (C57BL/6) sensitized and aerosol challenged with the allergen ovalbumin (OVA) or phosphate buffered saline (PBS) were treated with (R)-albuterol, (S)-albuterol or (R+S)-albuterol. Following administration of (R)-albuterol, allergen induced bronchoalveolar lavage eosinophils and IgE showed a decrease, albeit not significantly by ANOVA. As T cells are important in allergic inflammation, we asked whether (R+S), (R) or (S)-albuterol might differ in effects on T cells and on the activity of the inflammatory transcription factor NF-κB. In activated T cells, (R)-albuterol administration decreased levels of inflammatory cytokines and NF-κB activity. These studies suggest that (R)-albuterol decreases cytokine secretion and NF-κB activity in T cells

Childhood-onset Leber hereditary optic neuropathy

Background The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. Methods Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m. 3460G>A, m. 11778G>A or m. 14484T>C. Results In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m. 3460G>A and m. 14484T>C mutations compared with the m. 11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) >= 0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA Conclusions Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor.Peer reviewe

Clinical utility gene card for : inherited optic neuropathies including next-generation sequencing-based approaches

Non peer reviewe

GoBIS: An integrated framework to analyse the goal and business process perspectives in information systems

[EN] Context Organisational reengineering, continuous process improvement, alignment among complementary analysis perspectives, and information traceability are some current motivations to promote investment and scientific effort for integrating goal and business process perspectives. Providing support to integrate information systems analysis becomes a challenge in this complex setting. Objective The GoBIS framework integrates two goal and business process modelling approaches: i⁎ (a goal-oriented modelling method) and Communication Analysis (a communication-oriented business process modelling method). Method In this paper, we describe the methodological integration of both methods with the aim of fulfilling several criteria: i) to rely on appropriate theories; ii) to provide abstract and concrete syntaxes; iii) to provide scenarios of application; iv) to develop tool support; v) to provide demonstrable benefits to potential adopters. Results We provide guidelines for using the two modelling methods in a top-down analysis scenario. The guidelines are validated by means of a comparative experiment and a focus-group session with students. Conclusions From a practitioner viewpoint (modeller and/or analyst), the guidelines facilitate the traceability between goal and business process models, the experimental results highlight the benefits of GoBIS in performance and usability perceptions, and demonstrate an improvement on the completeness of the latter having an impact on efficiency. From a researcher perspective, the validation has produced useful feedback for future research.This work has been supported by the Spanish MICINN Project ProS-Req (TIN2010-19130-C02-01, TIN2010-19130-C02-02) and EOSSAC (TIN2013-44641-P); the Generalitat Valenciana Project IDEO (PROMETEOII/2014/039); the FPI-UPV Pre-Doctoral Grant; the European Commission Project CaaS (FP7 611351); and the ERDF Structural Funds.Ruiz Carmona, LM.; Costal, D.; España Cubillo, S.; Franch, X.; Pastor López, O. (2015). GoBIS: An integrated framework to analyse the goal and business process perspectives in information systems. Information Systems. 53:330-345. https://doi.org/10.1016/j.is.2015.03.007S3303455