tbuckley/cabot-search huggingface dataset:
Bystander Effects, Pharmacokinetics, and Linker-Payload Stability of EGFR-Targeting Antibody-Drug Conjugates Losatuxizumab Vedotin and Depatux-M in Glioblastoma Models
Authors: Sonia Jain, Jessica I. Griffith, Kendra A. Porath, Sneha Rathi, Jiayan Le, Tugce I. Pasa, Paul A. Decker, Shiv K. Gupta, Zeng Hu, Brett L. Carlson, Katrina Bakken, Danielle M. Burgenske, Thomas M. Feldsien, Didier R. Lefebvre, Rachael A. Vaubel, Jeanette E. Eckel-Passow, Edward B. Reilly, William F. Elmquist, Jann N. Sarkaria
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Antibody-drug conjugates (ADC) are targeted therapies with robust efficacy in solid cancers, and there is intense interest in using EGFR-specific ADCs to target EGFR-amplified glioblastoma (GBM). Given GBM’s molecular heterogeneity, the bystander activity of ADCs may be important for determining treatment efficacy. In this study, the activity and toxicity of two EGFR-targeted ADCs with similar auristatin toxins, Losatuxizumab vedotin (ABBV-221) and Depatuxizumab mafodotin (Depatux-M), were compared in GBM patient-derived xenografts (PDX) and normal murine brain following direct infusion by convection-enhanced delivery (CED). Experimental Design: EGFRviii-amplified and non-amplified GBM PDXs were used to determine in vitro cytotoxicity, in vivo efficacy, and bystander activities of ABBV-221 and Depatux-M. Nontumor-bearing mice were used to evaluate the pharmacokinetics (PK) and toxicity of ADCs using LC-MS/MS and immunohistochemistry. Results: CED improved intracranial efficacy of Depatux-M and ABBV-221 in three EGFRviii-amplified GBM PDX models (Median survival: 125 to &amp;gt;300 days vs. 20–49 days with isotype control AB095). Both ADCs had comparable in vitro and in vivo efficacy. However, neuronal toxicity and CD68+ microglia/macrophage infiltration were significantly higher in brains infused with ABBV-221 with the cell-permeable monomethyl auristatin E (MMAE), compared with Depatux-M with the cell-impermeant monomethyl auristatin F. CED infusion of ABBV-221 into the brain or incubation of ABBV-221 with normal brain homogenate resulted in a significant release of MMAE, consistent with linker instability in the brain microenvironment. Conclusions: EGFR-targeting ADCs are promising therapeutic options for GBM when delivered intratumorally by CED. However, the linker and payload for the ADC must be carefully considered to maximize the therapeutic window.
Germany's cannabis act: a catalyst for European drug policy reform?
Authors: Jakob Manthey, Jürgen Rehm, Uwe Verthein
Journal: The Lancet Regional Health - Europe (2024)

With the enforcement of the Cannabis Act on 1 April 2024, Germany has adopted one of the most liberal legal approaches to cannabis on the continent. The German model prioritises a non-profit approach and precludes legal market mechanisms. We believe these are the main drivers for increasing cannabis use and related health problems, based on observations following cannabis legalisation in Canada and many states in the U.S. Although legalising cannabis possession and cultivation may not immediately eliminate the illegal market, it is expected to serve public health goals. Despite the overall positive evaluation of the Cannabis Act in Germany, there are three potential areas of concern: the potential for misuse of the medical system, the normalization of cannabis use, and the influence of the cannabis industry. The German model may herald the beginning of a new generation of European cannabis policies, but concerted efforts will be required to ensure that these policy reforms serve rather than undermine public health goals.
Boundary effects cause false signals of range expansions in population genomic data
Authors: Petri Kemppainen, Rhiannon Schembri, Paolo Momigliano
Journal: Molecular Biology and Evolution (2024)

Abstract Studying range expansions is central for understanding genetic variation through space and time as well as for identifying refugia and biological invasions. Range expansions are characterized by serial founder events causing clines of decreasing genetic diversity away from the center of origin and asymmetries in the two-dimensional allele frequency spectra. These asymmetries, summarized by the directionality index (ψ), are sensitive to range expansions and persist for longer than clines in genetic diversity. In continuous and finite meta-populations, genetic drift tends to be stronger at the edges of the species distribution in equilibrium populations and populations undergoing range expansions alike. Such boundary effects are expected to affect geographic patterns in genetic diversity and ψ. Here we demonstrate that boundary effects cause high false positive rates in equilibrium meta-populations when testing for range expansions. In the simulations, the absolute value of ψ (|ψ|) in equilibrium data sets was proportional to the fixation index (FST). By fitting signatures of range expansions as a function of ɛ |ψ|/FST and geographic clines in ψ, strong evidence for range expansions could be detected in data from a recent rapid invasion of the cane toad, Rhinella marina, in Australia, but not in 28 previously published empirical data sets from Australian scincid lizards that were significant for the standard range expansion tests. Thus, while clinal variation in ψ is still the most sensitive statistic to range expansions, to detect true signatures of range expansions in natural populations, its magnitude needs to be considered in relation to the overall levels of genetic structuring in the data.
Joint shape/texture representation learning for cardiovascular disease diagnosis from MRI
Authors: Xiang Chen, Yan Xia, Erica Dall'Armellina, Nishant Ravikumar, Alejandro F Frangi
Journal:  (2024)

Abstract Aims Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Cardiac image and mesh are two primary modalities to present the shape and structure of the heart and have been demonstrated to be efficient in CVD prediction and diagnosis. However, previous research has been generally focussed on a single modality (image or mesh), and few of them have tried to jointly consider the image and mesh representations of heart. To obtain efficient and explainable biomarkers for CVD prediction and diagnosis, it is needed to jointly consider both representations. Methods and results We design a novel multi-channel variational auto-encoder, mesh-image variational auto-encoder, to learn joint representation of paired mesh and image. After training, the shape-aware image representation (SAIR) can be learned directly from the raw images and applied for further CVD prediction and diagnosis. We demonstrate our method on data from UK Biobank study and two other datasets via extensive experiments. In acute myocardial infarction prediction, SAIR achieves 81.43% accuracy, significantly higher than traditional biomarkers like metadata and clinical indices (left ventricle and right ventricle clinical indices of cardiac function like chamber volume, mass, and ejection fraction). Conclusion Our mesh-image variational auto-encoder provides a novel approach for 3D cardiac mesh reconstruction from images. The extraction of SAIR is fast and without need of segmentation masks, and its focussing can be visualized in the corresponding cardiac meshes. SAIR archives better performance than traditional biomarkers and can be applied as an efficient supplement to them, which is of significant potential in CVD analysis.
Comparing Flow And Pulmonary Artery Growth Post PDA Stenting In Patients With Ductal-Dependent Pulmonary Flow Using Four-Dimensional Magnetic Resonance Imaging (4D Flow MRI)
Authors: Faiza A Al Kindi, Hamood Al Kindi, Madan Mohan Maddali, Abdullah Al Farqani, Khalid Al Alawi, Abdullah Al Balushi, Mohammed Al Ghafri, Sahar Khalil, Satish Kumar
Journal:  (2024)

The 4D magnetic resonance imaging (4D-flow MRI) provides a qualitative and quantitative assessment of cardiovascular structures and processes. 4D-flow MRI was used to study pulmonary flow in post-patent ductus arteriosus (PDA) stent insertion in duct-dependent pulmonary flow neonates at baseline (PDA stent insertion) and after 6 months, and also, to evaluate the effect of flow dynamics on the growth of pulmonary arteries (PAs).
Evolution of chromosomal inversions across an avian radiation
Authors: Ulrich Knief, Ingo A Müller, Katherine F Stryjewski, Dirk Metzler, Michael D Sorenson, Jochen B W Wolf
Journal: Molecular Biology and Evolution (2024)

Chromosomal inversions are structural mutations that can play a prominent role in adaptation and speciation. Inversions segregating across species boundaries (trans-species inversions) are often taken as evidence for ancient balancing selection or adaptive introgression, but can also be due to incomplete lineage sorting. Using whole-genome resequencing data from 18 populations of 11 recognized munia species in the genus Lonchura (N = 176 individuals), we identify four large para- and pericentric inversions ranging in size from 4 to 20 Mb. All four inversions cosegregate across multiple species and predate the numerous speciation events associated with the rapid radiation of this clade across the prehistoric Sahul (Australia, New Guinea) and Bismarck Archipelago. Using coalescent theory, we infer that trans-specificity is improbable for neutrally segregating variation despite substantial incomplete lineage sorting characterizing this young radiation. Instead, the maintenance of all three autosomal inversions (chr1, chr5, and chr6) is best explained by selection acting along ecogeographic clines not observed for the collinear parts of the genome. In addition, the sex chromosome inversion largely aligns with species boundaries and shows signatures of repeated positive selection for both alleles. This study provides evidence for trans-species inversion polymorphisms involved in both adaptation and speciation. It further highlights the importance of informing selection inference using a null model of neutral evolution derived from the collinear part of the genome.
Granzyme B-activated IL18 potentiates αβ and γδ CAR T cell immunotherapy in a tumor-dependent manner
Authors: Caroline M Hull, Daniel Larcombe-Young, Roberta Mazza, Molly George, David M Davies, Anna Schurich, John Maher
Journal: Molecular Therapy (2024)

Interleukin (IL)18 is a potent pro-inflammatory cytokine that is activated upon caspase 1 cleavage of the latent precursor, pro-IL18. Therapeutic T cell armoring with IL18 promotes autocrine stimulation and positive modulation of the tumor microenvironment (TME). However, existing strategies are imperfect since they involve constitutive/poorly regulated activity or fail to modify the TME. Here, we have substituted the caspase 1 cleavage site within pro-IL18 with that preferred by granzyme B, yielding GzB-IL18. We demonstrate that GzB-IL18 is constitutively released but remains functionally latent unless chimeric antigen receptor (CAR) T cells are activated, owing to concomitant granzyme B release. Armoring with GzB-IL18 enhances cytolytic activity, proliferation, interferon (IFN)-γ release, and anti-tumor efficacy by a similar magnitude to constitutively active IL18. We also demonstrate that GzB-IL18 provides a highly effective armoring strategy for γδ CAR T cells, leading to enhanced metabolic fitness and significant potentiation of therapeutic activity. Finally, we show that constitutively active IL18 can unmask CAR T cell-mediated cytokine release syndrome in immunocompetent mice. By contrast, GzB-IL18 promotes anti-tumor activity and myeloid cell re-programming without inducing such toxicity. Using this stringent system, we have tightly coupled the biological activity of IL18 to the activation state of the host CAR T cell, favoring safer clinical implementation of this technology.
Barriers and enablers to a healthy lifestyle in people with infertility: a mixed-methods systematic review
Authors: Sophia Torkel, Rui Wang, Robert J Norman, Lijun Zhao, Kai Liu, Dana Boden, Wentong Xu, Lisa Moran, Stephanie Cowan
Journal: Human Reproduction Update (2024)

Abstract BACKGROUND While there is a recognized role of optimizing lifestyle (diet and physical activity) behaviours in the management of infertility, the best practice remains unknown and factors influencing the lifestyle of people with infertility are not well understood. OBJECTIVE AND RATIONALE This systematic review evaluated barriers and enablers to a healthy lifestyle in people with infertility, from the perspectives of people with infertility and health professionals, in order to inform optimal behavioural change strategies. SEARCH METHODS Ovid MEDLINE(R), PsycINFO, EMBASE, EBM Reviews, and CINAHL were searched from inception to 28 August 2023. Eligible studies were qualitative and quantitative primary studies that explored barriers and/or enablers to lifestyle for infertility management. Quality assessment was performed using the Centre for Evidence-Based Management Critical Appraisal of a Survey Tool and the Critical Appraisal Skills Programme Qualitative Checklist. Data were analysed by thematic analysis with themes mapped to the Capability, Opportunity, Motivation and Behaviour (COM-B) model and Theoretical Domains Framework (TDF). OUTCOMES After screening 12 326 abstracts and 99 full-texts, 27 studies were included (12 quantitative, 6 qualitative and 9 mixed-methods) with 22 studies of women with infertility (n = 2524), 11 studies of men with infertility (n = 1407), and 6 studies of health professionals (n = 372). We identified barriers and enablers relating to capability (e.g. strategies for behaviour change), opportunity (e.g. limited time, resources, and money), and motivation (e.g. interplay between lifestyle and emotional state). Based on the identified themes, suggested intervention components to integrate into lifestyle management of infertility include facilitating development of self-management skills to support lifestyle change (e.g. self-monitoring, action planning, and goal setting) and incorporating mental health strategies (e.g. providing information about the benefits of healthy lifestyle behaviours for mental health and encouraging patients to reframe healthy lifestyle behaviours as self-care strategies). WIDER IMPLICATIONS The findings have identified important factors that influence lifestyle management in people with infertility and have suggested relevant intervention components to consider when designing interventions. Given the paucity of qualitative studies identified, more research is needed to further understand the complex and interacting factors that shape lifestyle during the fertility journey.
Project Optimus Elicits the “Holistic” Benefits of PK/PD Modeling of Immunotherapy
Authors: Mathangi Gopalakrishnan, Rodabe N. Amaria
Journal: Clinical Cancer Research (2024)

Summary Leveraging a heterogeneous dataset, a recent article demonstrated the application of pharmacometric modeling to inform the dosing of nivolumab–relatlimab fixed-dose combination in special populations, including adolescents lacking clinical data. The use of model-informed approaches during clinical drug development can be cost-effective, which ensures fast access to drugs and enhances patient outcomes. See related article by Zhao et al., p. 3050
Localized translation and sarcomere maintenance requires ribosomal protein SA in mice
Authors: Rami Haddad, Omer Sadeh, Tamar Ziv, Itai Erlich, Lilac Haimovich-Caspi, Ariel Shemesh, Jolanda van der Velden, Izhak Kehat
Journal: Journal of Clinical Investigation (2024)

Cardiomyocyte sarcomeres contain localized ribosomes, but the factors responsible for their localization and the significance of localized translation are unknown. Using proximity labeling, we identified Ribosomal Protein SA (RPSA) as a Z-line protein. In cultured cardiomyocytes, the loss of RPSA led to impaired local protein translation and reduced sarcomere integrity. By employing CAS9 expressing mice along with adeno-associated viruses expressing CRE recombinase and single-guide RNAs targeting Rpsa, we knocked out Rpsa in vivo and observed mis-localization of ribosomes and diminished local translation. These genetic mosaic mice with Rpsa knockout in a subset of cardiomyocytes developed dilated cardiomyopathy, featuring atrophy of RPSA-deficient cardiomyocytes, compensatory hypertrophy of unaffected cardiomyocytes, left ventricular dilation, and impaired contractile function. We demonstrate that RPSA C-terminal domain is sufficient for localization to the Z-lines and that if the microtubule network is disrupted RPSA loses its sarcomeric localization. These findings highlight RPSA as a ribosomal factor essential for ribosome localization to the Z-line, facilitating local translation and sarcomere maintenance.
ZBP1-mediated apoptosis and inflammation exacerbate steatotic liver ischemia-reperfusion injury
Authors: Ran Liu, Huan Cao, Shuhua Zhang, Mao Cai, Tianhao Zou, Guoliang Wang, Di Zhang, Xueling Wang, Jianjun Xu, Shenghe Deng, Tongxi Li, Daichao Xu, Jinyang Gu
Journal: Journal of Clinical Investigation (2024)

There is increasing need to expand availability of donor liver grafts, including steatotic livers. However, the current use of steatotic grafts in liver transplantation is less acceptable due to their higher susceptibility to ischemia-reperfusion (I/R) injury. To investigate the mechanism underlying the susceptibility of steatotic liver to I/R injury, we detected cell death markers and inflammation in clinical donor livers and animal models. We found that caspase-8-mediated hepatic apoptosis is activated in steatotic liver I/R. However, ablation of caspase-8 only slightly mitigated steatotic liver I/R injury without affecting inflammation. We further demonstrated that RIPK1 kinase induces both caspase-8-mediated apoptosis and cell death-independent inflammation. Inhibition of RIPK1 kinase significantly protects against steatotic liver I/R injury by alleviating both hepatic apoptosis and inflammation. Additionally, we found that RIPK1 activation is induced by Z-DNA binding protein 1 (ZBP1) but not the canonical TNFα pathway during steatotic liver I/R. Deletion of ZBP1 substantially decreases the steatotic liver I/R injury. Mechanistically, ZBP1 is amplified by palmitic acid-activated JNK pathway in steatotic livers. Upon I/R, excessive reactive oxygen species trigger ZBP1 activation by inducing its aggregation independent of the Z-nucleic acids sensing action in steatotic livers, leading to the kinase activation of RIPK1 and the subsequent aggravation of liver injury. Thus, ZBP1-mediated RIPK1-driven apoptosis and inflammation exacerbate steatotic liver I/R injury, which could be targeted to protect steatotic donor livers during transplantation.
Epidemiology and Risk Factors of Eosinophilic Esophagitis in Japan: A Population-Based Study
Authors: Akinari Sawada, Takumi Imai, Yasutaka Ihara, Fumio Tanaka, Ikuo Hirano, Yasuhiro Fujiwara
Journal: Clinical Gastroenterology and Hepatology (2024)

Eosinophilic esophagitis (EoE) has been increasingly diagnosed globally. However, there have been few general population-based studies in Asia. The aim of this study was to investigate EoE epidemiology in the Japanese general population.
Extracellular vesicles in glioblastoma: Biomarkers and therapeutic tools
Authors: Ilaria Cela, Emily Capone, Gianluca Trevisi, Gianluca Sala
Journal: Seminars in Cancer Biology (2024)

Glioblastoma (GBM) is the most aggressive tumor among the gliomas and intracranial tumors and to date prognosis for GBM patients remains poor, with a median survival typically measured in months to a few years depending on various factors. Although standardized therapies are routinely employed, it is clear that these strategies are unable to cope with heterogeneity and invasiveness of GBM. Furthermore, diagnosis and monitoring of responses to therapies are directly dependent on tissue biopsies or magnetic resonance imaging (MRI) techniques. From this point of view, liquid biopsies are arising as key sources of a variety of biomarkers with the advantage of being easily accessible and monitorable. In this context, extracellular vesicles (EVs), physiologically shed into body fluids by virtually all cells, are gaining increasing interest both as natural carriers of biomarkers and as specific signatures even for GBM. What makes these vesicles particularly attractive is they are also emerging as therapeutical vehicles to treat GBM given their native ability to cross the blood-brain barrier (BBB). Here, we reviewed recent advances on the use of EVs as biomarker for liquid biopsy and nanocarriers for targeted delivery of anticancer drugs in glioblastoma.
Engineering of potent CAR NK cells using non-viral Sleeping Beauty transposition from minimalistic DNA vectors
Authors: Tobias Bexte, Lacramioara Botezatu, Csaba Miskey, Fenja Gierschek, Alina Moter, Philipp Wendel, Lisa Marie Reindl, Julia Campe, Jose Francisco Villena-Ossa, Veronika Gebel, Katja Stein, Toni Cathomen, Anjali Cremer, Winfried S. Wels, Michael Hudecek, Zoltán Ivics, Evelyn Ullrich
Journal: Molecular Therapy (2024)
Eye-Tracking Biomarkers and Autism Diagnosis in Primary Care
Authors: Brandon Keehn, Patrick Monahan, Brett Enneking, Tybytha Ryan, Nancy Swigonski, Rebecca McNally Keehn
Journal: JAMA Network Open (2024)

Importance Finding effective and scalable solutions to address diagnostic delays and disparities in autism is a public health imperative. Approaches that integrate eye-tracking biomarkers into tiered community-based models of autism evaluation hold promise for addressing this problem. Objective To determine whether a battery of eye-tracking biomarkers can reliably differentiate young children with and without autism in a community-referred sample collected during clinical evaluation in the primary care setting and to evaluate whether combining eye-tracking biomarkers with primary care practitioner (PCP) diagnosis and diagnostic certainty is associated with diagnostic outcome. Design, Setting, and Participants Early Autism Evaluation (EAE) Hub system PCPs referred a consecutive sample of children to this prospective diagnostic study for blinded eye-tracking index test and follow-up expert evaluation from June 7, 2019, to September 23, 2022. Participants included 146 children (aged 14-48 months) consecutively referred by 7 EAE Hubs. Of 154 children enrolled, 146 provided usable data for at least 1 eye-tracking measure. Main Outcomes and Measures The primary outcomes were sensitivity and specificity of a composite eye-tracking (ie, index) test, which was a consolidated measure based on significant eye-tracking indices, compared with reference standard expert clinical autism diagnosis. Secondary outcome measures were sensitivity and specificity of an integrated approach using an index test and PCP diagnosis and certainty. Results Among 146 children (mean [SD] age, 2.6 [0.6] years; 104 [71%] male; 21 [14%] Hispanic or Latine and 96 [66%] non-Latine White; 102 [70%] with a reference standard autism diagnosis), 113 (77%) had concordant autism outcomes between the index (composite biomarker) and reference outcomes, with 77.5% sensitivity (95% CI, 68.4%-84.5%) and 77.3% specificity (95% CI, 63.0%-87.2%). When index diagnosis was based on the combination of a composite biomarker, PCP diagnosis, and diagnostic certainty, outcomes were concordant with reference standard for 114 of 127 cases (90%) with a sensitivity of 90.7% (95% CI, 83.3%-95.0%) and a specificity of 86.7% (95% CI, 70.3%-94.7%). Conclusions and Relevance In this prospective diagnostic study, a composite eye-tracking biomarker was associated with a best-estimate clinical diagnosis of autism, and an integrated diagnostic model including PCP diagnosis and diagnostic certainty demonstrated improved sensitivity and specificity. These findings suggest that equipping PCPs with a multimethod diagnostic approach has the potential to substantially improve access to timely, accurate diagnosis in local communities.