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Introduction: Magnetic resonance imaging (MRI) segmentation algorithms make it possible to study detailed medial temporal lobe (MTL) substructures as hippocampal subfields and amygdala subnuclei, offering opportunities to develop biomarkers for preclinical Alzheimer's disease (AD)., Methods: We identified the MTL substructures significantly associated with tau-positron emission tomography (PET) signal in 581 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI-3). We confirmed our results in our UCLouvain cohort including 110 non-demented individuals by comparing volumes between individuals with different visual Braak's stages and clinical diagnosis., Results: Four amygdala subnuclei (cortical, central, medial, and accessory basal) were associated with tau in amyloid beta-positive (Aβ+) clinically normal (CN) individuals, while the global amygdala and hippocampal volumes were not. Using UCLouvain data, we observed that both Braak I-II and Aβ+ CN individuals had smaller volumes in these subnuclei, while no significant difference was observed in the global structure volumes or other subfields., Conclusion: Measuring specific amygdala subnuclei, early atrophy may serve as a marker of temporal tauopathy in preclinical AD, identifying individuals at risk of progression., Highlights: Amygdala atrophy is not homogeneous in preclinical Alzheimer's disease (AD). Tau pathology is associated with atrophy of specific amygdala subnuclei, specifically, the central, medial, cortical, and accessory basal subnuclei. Hippocampal and amygdala volume is not associated with tau in preclinical AD. Hippocampus and CA1-3 volume is reduced in preclinical AD, regardless of tau., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: There is good evidence that elevated amyloid-β (Aβ) positron emission tomography (PET) signal is associated with cognitive decline in clinically normal (CN) individuals. However, it is less well established whether there is an association between the Aβ burden and decline in daily living activities in this population. Moreover, Aβ-PET Centiloids (CL) thresholds that can optimally predict functional decline have not yet been established., Methods: Cross-sectional and longitudinal analyses over a mean three-year timeframe were performed on the European amyloid-PET imaging AMYPAD-PNHS dataset that phenotypes 1260 individuals, including 1032 CN individuals and 228 participants with questionable functional impairment. Amyloid-PET was assessed continuously on the Centiloid (CL) scale and using Aβ groups (CL < 12 = Aβ-, 12 ≤ CL ≤ 50 = Aβ-intermediate/Aβ± , CL > 50 = Aβ+). Functional abilities were longitudinally assessed using the Clinical Dementia Rating (Global-CDR, CDR-SOB) and the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q). The Global-CDR was available for the 1260 participants at baseline, while baseline CDR-SOB and A-IADL-Q scores and longitudinal functional data were available for different subsamples that had similar characteristics to those of the entire sample., Results: Participants included 765 Aβ- (61%, Mdn age  = 66.0, IQR age  = 61.0-71.0; 59% women), 301 Aβ± (24%; Mdn age  = 69.0, IQR age  = 64.0-75.0; 53% women) and 194 Aβ+ individuals (15%, Mdn age  = 73.0, IQR age  = 68.0-78.0; 53% women). Cross-sectionally, CL values were associated with CDR outcomes. Longitudinally, baseline CL values predicted prospective changes in the CDR-SOB (b CL*Time  = 0.001/CL/year, 95% CI [0.0005,0.0024], p = .003) and A-IADL-Q (b CL*Time  = -0.010/CL/year, 95% CI [-0.016,-0.004], p = .002) scores in initially CN participants. Increased clinical progression (Global-CDR > 0) was mainly observed in Aβ+ CN individuals (HR Aβ+ vs Aβ-  = 2.55, 95% CI [1.16,5.60], p = .020). Optimal thresholds for predicting decline were found at 41 CL using the CDR-SOB (b Aβ+ vs Aβ-  = 0.137/year, 95% CI [0.069,0.206], p < .001) and 28 CL using the A-IADL-Q (b Aβ+ vs Aβ-  = -0.693/year, 95% CI [-1.179,-0.208], p = .005)., Conclusions: Amyloid-PET quantification supports the identification of CN individuals at risk of functional decline., Trial Registration: The AMYPAD PNHS is registered at www.clinicaltrialsregister.eu with the EudraCT Number: 2018-002277-22., (© 2024. The Author(s).)

Type I interferon (IFN) is a potent antitumoral drug, with an important history in the treatment of hematologic malignancies. However, its pleiotropic nature leads to severe dose-limiting toxicities that blunt its therapeutic potential. To achieve selective targeting of specific immune or tumor cells, AcTakines (Activity-on-Target Cytokines), i.e., immunocytokines utilizing attenuated cytokines, and clinically optimized A-Kines™ were developed. In syngeneic murine models, the CD20-targeted murine IFNα2-based AcTaferons (AFNs) have demonstrated clear antitumoral effects, with excellent tolerability. The current study explores the antitumoral potential of the humanized huCD20-Fc-AFN in 5 different humanized patient derived xenograft (PDX) models of huCD20 + aggressive B non-Hodgkin lymphomas (B-NHLs). The huCD20-Fc-AFN consists of a huCD20-specific single-domain antibody (VHH) linked through a heterodimeric 'knob-in-hole' human IgG1 Fc molecule to an attenuated huIFNα2 sequence. An in vitro targeting efficacy of up to 1.000-fold could be obtained, without detectable in vivo toxicities, except for selective (on-target) and reversible B cell depletion. Treatment with huCD20-Fc-AFN significantly increased the median overall survival (mOS) in both non-humanized (mOS 31 to 45 days; HR = 0.26; p = 0.001), and humanized NSG/NOG mice (mOS 34 to 80 days; HR = 0.37; p < 0.0001). In humanized mice, there was a trend for increased survival when compared to equimolar rituximab (mOS 49 to 80 days; HR = 0.73; p = 0.09). The antitumoral effects of huCD20-Fc-AFN were partly due to direct effects of type I IFN on the tumor cells, but additional effects via the human immune system are essential to obtain long-term remissions. To conclude, huCD20-Fc-AFN could provide a novel therapeutic strategy for huCD20-expressing aggressive B-NHLs., (© 2024. The Author(s).)

Research Question: Clomiphene citrate (CC) is one of the first-line treatments for ovulation induction in women with anovulatory polycystic ovary syndrome (PCOS). However, nearly 1 out of 2 women is resistant to 50 mg/day of CC. The objective of this study is to investigate the clinical, biological, and/or ultrasound factors that may predict the resistance to 50 mg/day of CC in the first cycle of treatment in women with anovulatory PCOS. This would make it possible to identify PCOS patients to whom the dose of 100 mg/day would be offered as of the first cycle., Design: A retrospective and monocentric study was conducted on 283 women with anovulatory PCOS who required the use of ovulation induction with CC (903 cycles)., Results: During the first cycle of treatment, 104 patients (36.8%) were resistant to 50 mg/day of CC. Univariate regression analysis showed that patients who resisted 50 mg/day of CC had significantly higher BMI, waist circumference, serum levels of AMH, total testosterone, Δ4-androstenedione, 17-OHP, and insulin ( p < 0.05), compared to patients ovulating with this dose. Serum levels of SHBG were significantly lower in patients resistant to 50 mg/day ( p < 0.05). After multivariate analysis, only AMH and SHBG remained statistically significant ( p = 0.01 and p = 0.001, respectively). However, areas under the ROC curves were weak (0.59 and 0.68, respectively)., Conclusion: AMH and SHBG are the only two parameters significantly associated with the risk of resistance to 50 mg/day of CC. However, no satisfactory thresholds have been established to predict resistance to 50 mg CC.

Background: Clinical success of therapeutic cancer vaccines depends on the ability to mount strong and durable antitumor T cell responses. To achieve this, potent cellular adjuvants are highly needed. Interleukin-1β (IL-1β) acts on CD8 + T cells and promotes their expansion and effector differentiation, but toxicity and undesired tumor-promoting side effects hamper efficient clinical application of this cytokine., Methods: This 'cytokine problem' can be solved by use of AcTakines ( Ac tivity-on- Ta rget cyto kines ), which represent fusions between low-activity cytokine mutants and cell type-specific single-domain antibodies. AcTakines deliver cytokine activity to a priori selected cell types and as such evade toxicity and unwanted off-target side effects. Here, we employ subcutaneous melanoma and lung carcinoma models to evaluate the antitumor effects of AcTakines., Results: In this work, we use an IL-1β-based AcTakine to drive proliferation and effector functionality of antitumor CD8 + T cells without inducing measurable toxicity. AcTakine treatment enhances diversity of the T cell receptor repertoire and empowers adoptive T cell transfer. Combination treatment with a neovasculature-targeted tumor necrosis factor (TNF) AcTakine mediates full tumor eradication and establishes immunological memory that protects against secondary tumor challenge. Interferon-γ was found to empower this AcTakine synergy by sensitizing the tumor microenvironment to TNF., Conclusions: Our data illustrate that anticancer cellular immunity can be safely promoted with an IL-1β-based AcTakine, which synergizes with other immunotherapies for efficient tumor destruction., Competing Interests: Competing interests: Financial interests: NK and JT are affiliated and hold equity interests in Orionis Biosciences. The following patent applications are related to the work presented in this paper: WO/2015/007542: Targeted modified IL-1 family members. Applicants: VIB VZW, Universiteit Gent, Centre National de la Recherche Scientifique, Université Montpellier, Centre Hospitalier Regional Universitaire de Montpellier. Inventors: JT, SG, FP and GU This patent application describes IL-1β mutants with reduced bioactivity that can be activated by targeting. WO/2017/134306: CD8 binding agents. Applicants: Orionis Biosciences, VIB VZW, Universiteit Gent. Inventors: JT, AC, NK and SG. This patent application describes sdAbs that bind CD8 and that can be used to target mutant IL-1β to CTLs. WO/2015/007903: Targeted modified TNF family members. Applicants: VIB VZW, Universiteit Gent, Centre National de la Recherche Scientifique, Université Montpellier, Centre Hospitalier Regional Universitaire de Montpellier. This patent application describes TNF mutants with reduced bioactivity that can be activated by targeting. Inventors: JT, Jennyfer Bultinck, FP and GU. The authors have no other, nonfinancial, competing interests to declare., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Production of leavened bread dates to the second millennium BCE. Since then, the art of bread making has developed, yet the evolution of bread-associated microbial species remains largely unknown. Nowadays, leavened bread is made either by using a pure commercial culture of the yeast Saccharomyces cerevisiae or by propagating a sourdough-a mix of flour and water spontaneously fermented by yeasts and bacteria. We studied the domestication of S. cerevisiae originating from industrial sources and artisanal sourdoughs and tested whether different bread-making processes led to population divergence. We found that S. cerevisiae bakery strains are polyphyletic with 67% of strains clustering into two main clades: most industrial strains were tetraploid and clustered with strains having diverse origins, including beer. By contrast, most sourdough strains were diploid and grouped in a second clade of strains having mosaic genomes and diverse origins, including fruits and natural environments. They harbored a higher copy number of genes involved in maltose utilization, and a high level of gene flow from multiple contributors was detected. Bakery strains displayed higher CO 2 production than do strains from other domesticated lineages (such as beer and wine), revealing a specific phenotypic signature of domestication. Interestingly, industrial strains had a shorter fermentation onset than sourdough strains, which were better adapted to a sourdough-like environment, suggesting divergent selection by industrial and artisanal processes. Our results reveal that the domestication of bakery yeast has been accompanied by dispersion, hybridization, and divergent selection through industrial and artisanal processes., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Systemic toxicities have severely limited the clinical application of tumor necrosis factor (TNF) as an anticancer agent. Activity-on-Target cytokines (AcTakines) are a novel class of immunocytokines with improved therapeutic index. A TNF-based AcTakine targeted to CD13 enables selective activation of the tumor neovasculature without any detectable toxicity in vivo. Upregulation of adhesion markers supports enhanced T-cell infiltration leading to control or elimination of solid tumors by, respectively, CAR T cells or a combination therapy with CD8-targeted type I interferon AcTakine. Co-treatment with a CD13-targeted type II interferon AcTakine leads to very rapid destruction of the tumor neovasculature and complete regression of large, established tumors. As no tumor markers are needed, safe and efficacious elimination of a broad range of tumor types becomes feasible., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Transposable elements (TEs) are genomic parasites with major impacts on host genome architecture and host adaptation. A proper evaluation of their evolutionary significance has been hampered by the paucity of short scale phylogenetic comparisons between closely related species. Here, we characterized the dynamics of TE accumulation at the micro-evolutionary scale by comparing two closely related plant species, Arabidopsis lyrata and A. halleri ., Results: Joint genome annotation in these two outcrossing species confirmed that both contain two distinct populations of TEs with either 'recent' or 'old' insertion histories. Identification of rare segregating insertions suggests that diverse TE families contribute to the ongoing dynamics of TE accumulation in the two species. Orthologous TE fragments (i.e. those that have been maintained in both species), tend to be located closer to genes than those that are retained in one species only. Compared to non-orthologous TE insertions, those that are orthologous tend to produce fewer short interfering RNAs, are less heavily methylated when found within or adjacent to genes and these tend to have lower expression levels. These findings suggest that long-term retention of TE insertions reflects their frequent acquisition of adaptive roles and/or the deleterious effects of removing nearly neutral TE insertions when they are close to genes., Conclusion: Our results indicate a rapid evolutionary dynamics of the TE landscape in these two outcrossing species, with an important input of a diverse set of new insertions with variable propensity to resist deletion., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Hepatocyte growth factor (HGF) and its receptor MET represent validated targets for cancer therapy. However, HGF/MET inhibitors being explored as cancer therapeutics exhibit cytostatic activity rather than cytotoxic activity, which would be more desired. In this study, we engineered an antagonistic anti-MET antibody that, in addition to blocking HGF/MET signaling, also kills MET-overexpressing cancer cells by antibody-dependent cellular cytotoxicity (ADCC). As a control reagent, we engineered the same antibody in an ADCC-inactive form that is similarly capable of blocking HGF/MET activity, but in the absence of any effector function. In comparing these two antibodies in multiple mouse models of cancer, including HGF-dependent and -independent tumor xenografts, we determined that the ADCC-enhanced antibody was more efficacious than the ADCC-inactive antibody. In orthotopic mammary carcinoma models, ADCC enhancement was crucial to deplete circulating tumor cells and to suppress metastases. Prompted by these results, we optimized the ADCC-enhanced molecule for clinical development, generating an antibody (ARGX-111) with improved pharmacologic properties. ARGX-111 competed with HGF for MET binding, inhibiting ligand-dependent MET activity, downregulated cell surface expression of MET, curbing HGF-independent MET activity, and engaged natural killer cells to kill MET-expressing cancer cells, displaying MET-specific cytotoxic activity. ADCC assays confirmed the cytotoxic effects of ARGX-111 in multiple human cancer cell lines and patient-derived primary tumor specimens, including MET-expressing cancer stem-like cells. Together, our results show how ADCC provides a therapeutic advantage over conventional HGF/MET signaling blockade and generates proof-of-concept for ARGX-111 clinical testing in MET-positive oncologic malignancies., (©2015 American Association for Cancer Research.)

Overexpression of CD70 has been documented in a variety of solid and hematological tumors, where it is thought to play a role in tumor proliferation and evasion of immune surveillance. Here, we describe ARGX-110, a defucosylated IgG1 monoclonal antibody (mAb) that selectively targets and neutralizes CD70, the ligand of CD27.   ARGX-110 was generated by immunization of outbred llamas. The antibody was germlined to 95% human identity, and its anti-tumor efficacy was tested in several in vitro assays. ARGX-110 binds CD70 with picomolar affinity. In depletion studies, ARGX-110 lyses tumor cells with greater efficacy than its fucosylated version. In addition, ARGX-110 demonstrates strong complement-dependent cytotoxicity and antibody-dependent cellular phagocytosis activity. ARGX-110 inhibits signaling of CD27, which results in blocking of the activation and proliferation of Tregs. In a Raji xenograft model, administration of the fucosylated version of ARGX-110 resulted in a prolonged survival at doses of 0.1 mg/kg and above. The pharmacokinetics of ARGX-110 was tested in cynomolgus monkeys; the calculated half-life is 12 days. In conclusion, ARGX-110 is a potent blocking mAb with a dual mode of action against both CD70-bearing tumor cells and CD70-dependent Tregs. This antibody is now in a Phase 1 study in patients with advanced malignancies expressing CD70 (NCT01813539).