Roche (Switzerland)

Advancing chemical reaction prediction in data-scarce drug discovery with active and geometric deep learning

Abstract The success of generative molecular design depends on the synthetic accessibility of the molecules it creates. While computational models can help predict chemical reactions, their current effectiveness is limited by a lack of reference data and the difficulty of accurat...

Bernoulli amputation

A novel, stochastic approach to amputation, the process of introducing missing values to a complete dataset, is presented. It allows one to construct a wide variety of missingness patterns by only having to specify distributions of missingness indicators as opposed to specifying...

In vitro and in vivo model systems for Orthoflavivirus antiviral therapeutics: current landscape and strategic considerations

ABSTRACT Orthoflaviviruses represent an escalating global health challenge, encompassing a diverse group of arthropod-borne viruses that cause substantial morbidity and mortality worldwide. A critical bottleneck in drug discovery is identifying in vitro and in vivo models that ac...

Werner helicase inhibitor for advanced microsatellite instability solid tumors: a phase 1 trial

Abstract Werner syndrome helicase (WRN) is a synthetic lethal target for microsatellite instability (MSI) cancers. In part 1 of this ongoing first-in-human, phase 1 trial, escalating doses of RO7589831 (VVD-133214), a first-in-class, WRN covalent inhibitor, were evaluated in 88 p...

Real‐Time Monitoring of Mass and Mechanical Properties in Single Cells and Multicellular Spheroids

ABSTRACT Cell state, growth, and mechanics are tightly connected properties underpinned by fundamental biological processes. Yet methods to quantify them simultaneously under physiologically relevant conditions, at resolutions sufficient to follow (sub)cellular processes, are sti...

Early Intraretinal Fluid Reduction is Linked to Vision Gains in Patients with Diabetic Macular Edema

This analysis evaluated the impact of early intraretinal fluid (IRF) reduction on long-term visual outcomes in patients with diabetic macular edema (DME). This was a treatment-agnostic, post hoc analysis of pooled data from patients with DME in YOSEMITE/RHINE (NCT03622580/NCT0362...

Early Macular Leakage Resolution Is Associated with Extended Faricimab Dosing in Retinal Vein Occlusion: A BALATON/COMINO Post Hoc Analysis

Macular leakage (ML) is a biomarker of disease activity and, in retinal vein occlusion (RVO), is associated with poor vision outcomes. Faricimab, a dual angiopoietin-2 (Ang-2)/vascular endothelial growth factor (VEGF)-A inhibitor, has demonstrated efficacy and durability in RVO....

CNS distribution and preclinical activity of the PI3K/AKT inhibitors inavolisib and ipatasertib in pediatric-type diffuse high-grade gliomas

Abstract Purpose Pediatric-type diffuse high-grade gliomas (pHGG) are aggressive, largely incurable malignancies often characterized by PI3K/AKT pathway activation. This study investigated whether the PI3K inhibitor inavolisib and the AKT inhibitor ipatasertib could achieve thera...

VEGF ‐A Antisense Oligonucleotide Therapy Inhibits Corneal Neovascularisation and Enhances Graft Survival in Murine High‐Risk Corneal Transplantation

BACKGROUND: To investigate, for the first time, whether an unconjugated VEGF-A antisense oligonucleotide (ASO) can inhibit corneal neovascularisation and improve graft survival in a murine high-risk corneal transplantation model. METHODS: A suture-induced corneal neovascularisati...

Barriers and enablers for health system reform

Introduction Health systems worldwide face escalating pressure from the growing burden of non-communicable diseases and population ageing, as well as chronic workforce shortages, infrastructure limitations, and structural misalignment between care models designed for acute illnes...

The Governance Gap: Democratizing Drug Development Through Decision Architecture

Drug development is most exposed to governance failure where it can least afford it, in global health. The field has more predictive power than at any point in its history and roughly the same failure rate it had a decade ago. We argue that this paradox persists because the field...

From feasibility to neuroanatomic validity of remote cognitive smartphone assessments in early Alzheimer’s disease

ABSTRACT Digital health technologies (DHT) offer a promising solution to the timely identification of early Alzheimer’s disease (eAD) to enable early treatment. This study evaluated the feasibility, acceptability, adherence, reliability, and preliminary clinical and content valid...

Assessing drug-induced liver injury liabilities in human and animal hepatocytes under static and perfused spheroid culture conditions

Abstract Drug-induced liver injury (DILI) remains a major challenge in drug development, highlighting the need for reliable in vitro tools to assess hepatotoxicity and improve translation from animal to human studies. Models using hepatocytes from preclinical species are also nee...

The vocal repertoire of white-nosed coatis: structural features, temporal dynamics, and social variations

Abstract For many group living species, vocal signals are a vital form of communication needed to coordinate social behaviours. Investigating these processes first requires a detailed description of the species’ vocal repertoire. White-nosed coatis ( Nasua narica ), which forage...

Autologous hematopoietic stem cell transplantation stabilizes retinal atrophy in multiple sclerosis

Abstract Autologous hematopoietic stem cell transplantation (aHSCT) is an effective treatment for aggressive multiple sclerosis refractory to disease-modifying therapies. Yet, its impact on neurodegeneration remains underexplored, and few predictive biomarkers for clinical outcom...

Estimating differing causal roles of glutamate and GABA genes on brain and behavior in autism

Abstract The excitatory/inhibitory (E/I) imbalance theory suggests that excitatory and inhibitory alterations underlies autism characteristics. However, genetic underpinnings of this imbalance and its impact on brain function and behavior remains unclear. We explored causal links...

A community-validated tool for clinical outcome calculation in multiple sclerosis: Consensus development and scenario-specific recommendations

Background: Reproducibility and comparability of disability outcomes remain major challenges in multiple sclerosis (MS) research. Definitions of disability progression vary widely across studies, and calculation criteria are often insufficiently documented to enable replication....

Data-driven construction of an imine reductase library capable of broad-scope reductive amination at equimolar substrate concentrations

Reductive amination catalysed by imine reductases and reductive aminases has emerged as a powerful method for the asymmetric synthesis of chiral amines, yet the generality and practical limitations of these enzymes remain poorly understood. Here, we combine large-scale, iterative...

Neurobiological correlates of longitudinal grey matter volume changes in preclinical Alzheimer’s disease

Background: Structural brain changes during the earliest asymptomatic stages of Alzheimer's disease (AD) remain poorly understood. Previous research in preclinical AD shows heterogeneous findings, reporting both subtle neuronal loss and paradoxical increases in grey matter (GM) v...

Early functional reactivity to a CEACAM5 x CD3 T cell bispecific antibody in solid tumors associates with baseline immune contexture rather than target antigen density alone

Abstract Clinical translation of T cell bispecific (TCB) therapies in solid tumors is hindered by the immunosuppressive tumor microenvironment and intratumoral heterogeneity, features poorly captured by standard preclinical models. We applied an integrated translational framework...