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Why is there no treatment for OA - Opportunity for AI based big data analytics to advance the field
No full textBackground: Osteoarthritis (OA) has been researched for decades but insights have not translated into a treatment for OA. One reason may be the heterogeneity of patients suffering from OA. Machine-learning (ML) could be leveraged to detect patterns of patient characteristics that allow stratification and the development of surrogate endpoints to improve trial designs and translate scientific advances to tangible benefits for patients.
Opportunity: The article describes the vision of collaborative inter-professional, inter-institutional as well as public-private activity leveraging the wealth of data to achieve this goal. We summarize the underlying assumptions, challenges and potential applications of a ML-based approach.
Use cases: Employing federated approach training algorithms locally has the advantage of preserving privacy. The application of novel ML techniques to divers sets of multidimensional health care data such as registries, real-world evidence, trial data etc. allows not only prognostic and predictive inferences but can also overcome issues with incompleteness of variables, heterogeneity in database structures and multidimensionality of variables. This exploration of data can form the foundation for the development of covariates, digital twins, synthetic control groups and form a potential basis for trial emulation. In addition, the approach will enable the development of novel (surrogate) endpoints and inform enrichment strategies.
Conclusion: Leveraging ML, the richness of data on OA and the expertise from various areas including patients, providers, ethicists and regulators has the potential to revolutionize trial designs in OA and finally meet the needs of patients suffering from OA
Beyond Eye Changes in Ocular Toxicity Studies: Practical Considerations for Sampling and Evaluation of Extraocular Visual Pathways, and Common Findings.
No full textOcular toxicity studies may encompass a variety of ocular routes of administration. Because the retina and optic nerve are an extension of the central nervous system, safety assessment of ocular compounds must include thorough examination of extraocular visual pathways, as ocular administration may result in primary toxicities in the nervous system due to its exposure to therapeutics via the retina and optic nerve, or changes that are secondary to primary ocular effects. Here we provide a practical guide to sampling extraocular visual pathway structures for commonly utilized ocular toxicology species (NHP, rabbit and rat) that is appropriate for implementation on the scale of preclinical ocular toxicity studies, highlighting examples of central nervous system toxicities following ocular administration of therapeutics. We discuss additional structures such as the ciliary ganglia, and oculomotor nerves, which may exhibit toxicities subsequent to administration of some ocular therapeutics and consider when these structures should be evaluated. Finally, we highlight special stains and molecular pathology tools, such as immunohistochemistry and in situ hybridization, and their utility in the investigation of primary (direct) or secondary toxicities present in extraocular visual pathways following ocular administration of a drug
Transforming atrial fibrillation management by targeting comorbidities and reducing atrial fibrillation burden: the 10th AFNET/EHRA consensus conference.
No full textAtrial fibrillation (AF) is a growing unmet medical need. To reduce its impact on patients' lives, improvements in stroke prevention therapy, treatment of concomitant conditions, and rhythm control therapy are actively developed: Innovations in anti-thrombotic agents, new anti-arrhythmic drugs (AADs), and novel interventional rhythm control therapies emerge alongside AF-reducing effects of general cardiometabolic therapies. Simple risk scores are slowly replaced by personalized AF risk estimation using quantifiable features. These developments were discussed by over 80 experts from academia and industry during the 10th Atrial Fibrillation NETwork /European Heart Rhythm Association consensus conference from 5 to 7 May 2025. The emerging consensus, described here, is multi-domain therapy combining stroke prevention, rhythm control, and therapy of concomitant cardiovascular conditions. This combines anti-coagulants, AADs, and AF ablation with old and new cardiometabolic drugs that can reduce AF risk, AF burden, and AF-related complications at scale. The paper furthermore describes quantitative traits that may enable a shift towards risk-driven therapy based on AF phenotypes. These can enable adjusted therapy strategies that are safe, accessible, and patient-centred. Applying modern data science and artificial intelligence methods to quantitative phenotypic and genetic features can further improve risk estimation and personalized therapy selection. At the same time, translational and clinical research into reversing the drivers of AF and into improved stroke prevention through new drugs and through combination therapies is needed. Together, these efforts offer pathways towards personalized, patient-centred, multi-modal, and accessible AF management that integrates rhythm control, stroke prevention, and therapy of concomitant conditions to bridge today's practical needs with tomorrow's therapeutic innovation
Genomic mediators of acquired resistance to immunotherapy in metastatic melanoma.
No full textAlthough some patients with metastatic melanoma experience durable responses to immune checkpoint inhibitors (ICIs), most exhibit intrinsic or acquired resistance to these therapies. Here, we compare somatic genomic profiles from matched pre-treatment and post-resistance tumor biopsies in patients (n = 25) with metastatic melanoma who exhibited heterogeneous ICI responses to nominate additional mediators of acquired resistance. We find that several acquired resistance tumors exhibit defects in B2M or JAK1/2, consistent with prior findings. We also discover resistance-associated mutations in SEC24C and SEC24D in 3 patients. SEC24 has an essential role in the trafficking of the dsDNA sensor STING and has been linked to interferonopathies. Melanoma cells engineered to express the SEC24C mutations observed in patients exhibit diminished STING signaling, including decreased type I interferon production, antigen presentation, and a reduced capacity to activate cytotoxic T cells. This study nominates a role for aberrant STING trafficking in acquired resistance to ICIs
Revealing Unpredicted Aspartic Acid Isomerization Hotspots by Probing Diagnostic Fragmentation Propensities in Top-Down and Middle-Down Mass Spectrometry.
No full textIsomerization of aspartic acid residues is a relevant degradation pathway of protein biopharmaceuticals as it can impair their biological activity. However, the in silico prediction of isomerization hotspots and their consequences remains ambiguous and misleading. We have previously shown that all ion differential analysis (AiDA) of middle-down spectra can be used to reveal diagnostic terminal and internal fragments with more sensitivity than the conventional fragment ion mass matching methodology. In this study, we use AiDA to characterize the degradation of an antibody fragment at three aspartic acid isomerization sites including a novel DW motif directly with electron-transfer/higher-energy collisional dissociation top-down and middle-down mass spectrometry. We show that AiDA methodology is pivotal to probe diagnostic fragmentation propensities of terminal c and z fragments at the N-terminus and vicinity of isomerization sites in addition to the diagnostic c+57 terminal fragments. Furthermore, AiDA can probe remote structural changes in the loop of an antibody complementarity-determining region induced by isomerization and the succinimide intermediate, revealing interactions between residues in agreement with molecular simulations. This study shows that aspartic acid residues at noncanonical DW and DF motifs can be hotspots for isomerization despite being ranked as false positives in physics-based prediction models. We show that the enzyme-free, fast, and sensitive AiDA methodology can be used as an orthogonal technique to fractionation for online variant characterization
Do networking and diversity elements impact the development of innovation leaders? A climate analysis in the pharmaceutical industry
No full textThere is compelling evidence that professional networks play a key role in career advancement through provision of mentoring experiences and the additive impact of domain-based expertise. It is also postulated that women and men often form different types of networks as defined by their structure (number of nodes, inner circles), how they function (cooperative, hierarchical) and are utilized (counselling, sociopolitical). In this climate analysis we investigated network dynamics of a representative cross section of women in innovation, scientific, and engineering roles in a global pharmaceutical company (WISE). Through a combination of quantitative (anonymous survey) and qualitative (interview based) measures we highlight differences in approach which were largely driven by career aspirations among respondents. Among individuals reporting rapid career advancement through verticals, rather than identifying mentoring interactions they highlighted diversity of experiences as a major factor. These include cross domain and cross-cultural experiences, job rotations, and experience in multi-disciplinary projects. The findings may have value in coaching and mentoring programs and in new employee onboarding programs
Enantioselective Palladium-Catalyzed α-Arylation of Acyclic Esters.
No full textA Pd-catalyzed enantioselective α-arylation of α,α-disubstituted esters with aryl bromides is established for the first time by employing P-chiral monophosphorus ligand 3-Pent-BIDIME as chiral ligand, leading to a series of enantioenriched α,α-diaryl esters possessing quaternary carbon stereocenters in moderate to good yields and high enantioselectivities. The method features a broad substrate scope, mild conditions, excellent functional group compatibility, and low Pd loadings (as low as 1 mol %). The synthetic power of this protocol is exemplified by efficient preparation of a chiral α,α-diaryl substituted γ-lactone and asymmetric synthesis of (R)-amolanone. DFT calculation revealed a NaBr-bridged downstream transmetalation and the importance of noncovalent interaction in controlling the enantioselectivity
First-in-human study of FAZ053, an anti-programmed death-ligand 1 (anti-PD-L1) monoclonal antibody, alone and in combination with spartalizumab (anti-PD-1), in patients with advanced malignancies
No full textFAZ053 triggers an antitumor response by targeting programmed death-ligand 1 (PD-L1), thereby activating effector T cells and negatively regulating T cells. This study assessed the safety, tolerability, and preliminary efficacy of FAZ053 monotherapy and in combination with spartalizumab in patients with advanced solid tumors.This phase I, multicenter, open-label study (NCT02936102) included dose escalation and dose expansion. The primary objectives were safety and tolerability; secondary objectives were pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.Of the 154 patients treated, 49 (52.7%) patients receiving FAZ053 monotherapy experienced at least one treatment-related adverse event (TRAE), of whom 6 (6.5%) experienced grade ≥3 TRAEs; 35 patients (57.4%) receiving combination therapy experienced TRAEs, of whom 3 (4.9%) experienced grade ≥3 TRAEs. One patient who received FAZ053 1600 mg every 6 weeks (Q6W) and one who received FAZ053 20 mg every 3 weeks (Q3W) with spartalizumab 300 mg Q3W experienced dose-limiting toxicities of grade 4 creatinine increase and grade 3 liver function test increased, respectively. The median duration of exposure was 105 days for monotherapy and 85 days for combination therapy. During dose escalation, response was observed in 3 (5.1%) and 3 (4.9%) patients receiving FAZ053 monotherapy and combination therapy, respectively. In dose expansion, response was observed in 2 (50%) patients with advanced alveolar soft part sarcoma (ASPS) and 3 (30%) patients with advanced chordoma receiving FAZ053 monotherapy. FAZ053 demonstrated a dose-proportional pharmacokinetic profile with a terminal half-life of 20.6 days at 1200 mg Q3W. Biomarker analysis showed increased immune gene expression following FAZ053 treatment. The recommended dose for expansion was 1200 mg Q3W.FAZ053 monotherapy was well tolerated and effective in maintaining disease control in various tumors including ASPS and chordoma. The anticipated synergistic effect of combined programmed cell death protein 1 (PD-1) and PD-L1 inhibition was not observed. These findings contribute to the growing evidence that rare, phenotypically 'immune cold' sarcomas, such as ASPS and chordoma, can become responsive to immune checkpoint inhibitors
Neurobiomarkers: Basic Aspects and their Relevance in Nonclinical Studies
No full textThe second session of the 2024 European Society of Toxicologic Pathology (ESTP) Congress highlighted the significance of neural biomarkers and functional endpoints in nonclinical studies for detecting acute or delayed peripheral (PNS) and central nervous system (CNS) alterations and /or injury caused by drugs during development. The session emphasized the potential clinical translation of these biomarkers and endpoints and critical role of pathologists in correlating these biomarkers with the microscopic findings. Key neural biomarkers discussed included fluid-based biomarkers such as Neurofilament Light Chain (NF-L), Nonspecific Enolase (NSE), Tubulin Associated Unit (TAU), and Glial Fibrillar Associated Protein (GFAP) in blood and/or Cerebrospinal fluid (CSF). These were evaluated in 15 in-vivo studies conducted with CNS and PNS toxicants. Safety pharmacology evaluation, such as the Irwin screen/the functional observation battery (FOB), were presented for detecting drug effects on behavior, motor and sensory functions in both rodents and non-rodent species, with or without histopathological correlate. Follow-up tests like nerve conduction velocity assessment were also highlighted. The session underscored the usefulness of non-invasive imaging modalities, including magnetic resonance imaging (MRI), nuclear imaging techniques, X-ray computed tomography and ultrasound in preclinical studies. Overall, integrating neural biomarkers, safety pharmacology endpoints, advanced imaging modalities, and detailed histopathological analysis aids in better predicting neurotoxicity
An ANGPTL4 inhibitory antibody safely improves lipid profiles in non-human primates.
No full textAngiopoietin-like protein 4 (ANGPTL4) inhibition is a promising approach to manage atherogenic dyslipidaemia and residual atherosclerotic cardiovascular disease (ASCVD) risk. Human ANGPTL4 loss-of-function (LoF) is associated with reduced plasma triglyceride (TG), remnant cholesterol (RC), and apolipoprotein B (ApoB) levels, and lower risk of type 2 diabetes and ASCVD, without observable safety concerns. However, development of ANGPTL4 inhibitors has been stalled by adverse findings in Angptl4 knockout mice fed a high-saturated-fat diet (HSFD), which show lipid accumulation in mesenteric lymph nodes (MLNs), systemic inflammation, severe adverse clinical signs, and reduced survival.Here, we present the development and preclinical characterisation of MAR001, a humanised monoclonal ANGPTL4 inhibitor antibody. We assessed single-dose MAR001 efficacy in hypertriglyceridemic (HTG) non-human primates (NHPs, n = 4), and safety in two NHP toxicology studies: a 15-week subchronic study with a standard or HSFD (n = 36), and a 9-month chronic study exclusively on an HSFD (n = 24).In HTG monkeys, single-dose MAR001 treatment reduced plasma TG by up to 58%, non-high-density lipoprotein cholesterol by 38%, ApoB by 30%, and RC by 59%. In safety studies, MAR001 was well tolerated without clinically adverse findings with either diet. Animals fed an HSFD exhibited minimal to moderate foamy macrophage formation in MLNs, but importantly, these histological findings did not progress to degeneration, necrosis, inflammation, fibrosis, or other reactive changes, and with no evidence of systemic effects, including no evidence of systemic inflammation or clinical adverse signs.MAR001 improved plasma lipid profiles in NHPs without clinical adversity, even during prolonged HSFD feeding. The favourable NHP safety profile aligns with human ANGPTL4 LoF findings, and contrasts with the severe pathology in mouse knockout models on an HSFD. These findings supported MAR001 clinical studies reported in our concurrent publication, which demonstrated robust lipid improvements without lymphatic pathology. Overall, these findings support continued development of MAR001 as a promising new therapy for ASCVD risk reduction.Marea Therapeutics