EHMT1/2 inhibition promotes regression of therapy-resistant ovarian cancer tumors in a CD8 T cell-dependent manner.

Poly ADP-ribose polymerase inhibitors (PARPi) are first-line maintenance therapy for ovarian cancer and an alternative therapy for several other cancer types. However, PARPi-resistance is rising and there is currently an unmet need to combat PARPi-resistant tumors. Here, we created an immunocompetent, PARPi-resistant mouse model to test the efficacy of combinatory PARPi and euchromatic histone methyltransferase 1/2 inhibitor (EHMTi) in the treatment of PARPi-resistant ovarian cancer. We discovered that inhibition of EHMT1/2 resensitizes cells to PARPi. Markedly, we show that single EHMTi and combinatory EHMTi/PARPi significantly reduced PARPi-resistant tumor burden and that this reduction is partially dependent on CD8 T cells. Altogether, our results show a low-toxicity drug that effectively treats PARPi-resistant ovarian cancer in an immune-dependent manner, supporting its entry into clinical development and potential incorporation of immunotherapy. Implications: Targeting the epigenome of therapy-resistant ovarian cancer induces an anti-tumor response mediated in part through an anti-tumor immune response.

Impact of NPSR1 gene variation on the neural correlates of phasic and sustained fear in spider phobia - an imaging genetics and independent replication approach.

The functional neuropeptide S receptor 1 (NPSR1) gene A/T variant (rs324981) is associated with fear processing. We investigated the impact of NPSR1 genotype on fear processing and on symptom reduction following treatment in individuals with spider phobia. A replication approach was applied (discovery sample: Münster (MS) nMS=104; replication sample Würzburg (WZ) nWZ=81). Participants were genotyped for NPSR1 rs324981 (T-allele carriers [risk] versus AA homozygotes [no-risk]). A sustained and phasic fear paradigm was applied during functional magnetic resonance imaging. A one-session virtual reality exposure treatment (VRET) was conducted. Change of symptom severity from pre to post treatment and within session fear reduction were assessed. T-allele carriers in the discovery sample displayed lower anterior cingulate cortex (ACC) activation compared to AA homozygotes independent of condition. For sustained fear, this effect was replicated within a small cluster and medium effect size. No association with symptom reduction was found. Within-session fear reduction was negatively associated with ACC activation in T-allele carriers in the discovery sample. NPSR1 rs324981 genotype might be associated with fear processing in the ACC in spider phobia. Interpretation as potential risk-increasing function of the NPSR1 rs324981 T-allele via impaired top-down control of limbic structures remains speculative. Potential association with symptom reduction warrants further research.

Childhood maltreatment and transdiagnostic connectivity of the default-mode network: The importance of duration of exposure.

Childhood maltreatment (CM) has been demonstrated to be associated with changes in resting-state functional connectivity of the default-mode network (DMN) across various mental disorders. Growing evidence regarding severity of CM is available but transdiagnostic research considering the role of both severity and duration of CM for DMN connectivity at rest is still scarce. We recruited a sample of participants with varying levels of CM suffering from three disorders in which a history of CM is frequently found, namely, post-traumatic stress disorder, major depressive disorder, or somatic symptom disorder, as well as healthy volunteers to examine DMN connectivity in a transdiagnostic sample. We expected to find changes in inter-network connectivity of the DMN related to higher self-reported levels of CM severity and duration. Resting-state functional magnetic resonance imaging scans of 128 participants were analyzed focusing on regions of interest (ROI-to-ROI approach) and whole-brain Seed-to-Voxel analyses with retrospectively assessed CM as predictor in a regression model. Changes in connectivity between nodes of the DMN and the visual network were identified to be associated with CM duration but not severity. CM duration showed associations with increased connectivity of the precuneus and visual regions, as well as sensory-motor regions. The observed changes in connectivity could be interpreted as an impairment of information transfer between the transmodal DMN and unimodal visual and sensory-motor regions with impairment increasing with duration of exposure to CM.

Claudin-4 Modulates Autophagy via SLC1A5/LAT1 as a Mechanism to Regulate Micronuclei.

Genome instability is a hallmark of cancer crucial for tumor heterogeneity and is often a result of defects in cell division and DNA damage repair. Tumors tolerate genomic instability, but the accumulation of genetic aberrations is regulated to avoid catastrophic chromosomal alterations and cell death. In ovarian cancer tumors, claudin-4 is frequently upregulated and closely associated with genome instability and worse patient outcomes. However, its biological association with regulating genomic instability is poorly understood. Here, we used CRISPR interference and a claudin mimic peptide to modulate the claudin-4 expression and its function in vitro and in vivo. We found that claudin-4 promotes a tolerance mechanism for genomic instability through micronuclei generation in tumor cells. Disruption of claudin-4 increased autophagy and was associated with the engulfment of cytoplasm-localized DNA. Mechanistically, we observed that claudin-4 establishes a biological axis with the amino acid transporters SLC1A5 and LAT1, which regulate autophagy upstream of mTOR. Furthermore, the claudin-4/SLC1A5/LAT1 axis was linked to the transport of amino acids across the plasma membrane as one of the potential cellular processes that significantly decreased survival in ovarian cancer patients. Together, our results show that the upregulation of claudin-4 contributes to increasing the threshold of tolerance for genomic instability in ovarian tumor cells by limiting its accumulation through autophagy. SIGNIFICANCE: Autophagy regulation via claudin-4/SLC1A5/LAT1 has the potential to be a targetable mechanism to interfere with genomic instability in ovarian tumor cells.

Lack of evidence for predictive utility from resting state fMRI data for individual exposure-based cognitive behavioral therapy outcomes: A machine learning study in two large multi-site samples in anxiety disorders.

Data-based predictions of individual Cognitive Behavioral Therapy (CBT) treatment response are a fundamental step towards precision medicine. Past studies demonstrated only moderate prediction accuracy (i.e. ability to discriminate between responders and non-responders of a given treatment) when using clinical routine data such as demographic and questionnaire data, while neuroimaging data achieved superior prediction accuracy. However, these studies may be considerably biased due to very limited sample sizes and bias-prone methodology. Adequately powered and cross-validated samples are a prerequisite to evaluate predictive performance and to identify the most promising predictors. We therefore analyzed resting state functional magnet resonance imaging (rs-fMRI) data from two large clinical trials to test whether functional neuroimaging data continues to provide good prediction accuracy in much larger samples. Data came from two distinct German multicenter studies on exposure-based CBT for anxiety disorders, the Protect-AD and SpiderVR studies. We separately and independently preprocessed baseline rs-fMRI data from n = 220 patients (Protect-AD) and n = 190 patients (SpiderVR) and extracted a variety of features, including ROI-to-ROI and edge-functional connectivity, sliding-windows, and graph measures. Including these features in sophisticated machine learning pipelines, we found that predictions of individual outcomes never significantly differed from chance level, even when conducting a range of exploratory post-hoc analyses. Moreover, resting state data never provided prediction accuracy beyond the sociodemographic and clinical data. The analyses were independent of each other in terms of selecting methods to process resting state data for prediction input as well as in the used parameters of the machine learning pipelines, corroborating the external validity of the results. These similar findings in two independent studies, analyzed separately, urge caution regarding the interpretation of promising prediction results based on neuroimaging data from small samples and emphasizes that some of the prediction accuracies from previous studies may result from overestimation due to homogeneous data and weak cross-validation schemes. The promise of resting-state neuroimaging data to play an important role in the prediction of CBT treatment outcomes in patients with anxiety disorders remains yet to be delivered.

Understanding the factors associated with COVID-19 vaccine hesitancy in Venezuela.

BACKGROUND: Despite nearly a quarter of Venezuelans remaining unvaccinated against coronavirus disease 2019 (COVID-19), the factors contributing to vaccine hesitancy in the country have not been thoroughly investigated. METHODS: A cross-sectional study was conducted from October 15th to 30th, 2022, using a knowledge, attitudes, and practices (KAP) survey to identify factors associated with COVID-19 vaccine hesitancy. RESULTS: The study analyzed data from 1,930 participants from all 24 states of Venezuela. The majority (93.4%) were vaccinated. The mean age was 40 years, predominantly female (67.3%), and held a university degree (70.6%). The mean KAP score was significantly higher among vaccinated individuals compared to unvaccinated ones (7.79 vs. 3.94 points for knowledge, 40 vs. 24 points for attitudes, and 16 vs. 10 points for practices, all p < 0.001). Increases in the scores for KAP were associated with increased odds of being vaccinated (84.6%, 25.6%, and 33% respectively for each one-point increase, all p < 0.001). Certain demographic factors such as marital status, occupation, religious beliefs, monthly income, and location influence COVID-19 vaccine knowledge. Higher income and certain occupations decrease the odds of low knowledge, while residing in specific states increases it. Attitudes towards the COVID-19 vaccine are influenced by age, health status, vaccination status, and location. Higher income and absence of certain health conditions decrease the odds of negative attitudes. Lastly, age, occupation, monthly income, and location affect vaccine practices. Advanced age and higher income decrease the odds of inappropriate practices, while residing in La Guaira state increases them. CONCLUSION: Factors such as age, education level, occupation, monthly income, and location were found to be associated with knowledge and attitudes towards COVID-19 vaccine among the surveyed Venezuelans.

Association between resting-state connectivity patterns in the defensive system network and treatment response in spider phobia-a replication approach.

Although highly effective on average, exposure-based treatments do not work equally well for all patients with anxiety disorders. The identification of pre-treatment response-predicting patient characteristics may enable patient stratification. Preliminary research highlights the relevance of inhibitory fronto-limbic networks as such. We aimed to identify pre-treatment neural signatures differing between exposure treatment responders and non-responders in spider phobia and to validate results through rigorous replication. Data of a bi-centric intervention study comprised clinical phenotyping and pre-treatment resting-state functional connectivity (rsFC) data of n = 79 patients with spider phobia (discovery sample) and n = 69 patients (replication sample). RsFC data analyses were accomplished using the Matlab-based CONN-toolbox with harmonized analyses protocols at both sites. Treatment response was defined by a reduction of >30% symptom severity from pre- to post-treatment (Spider Phobia Questionnaire Score, primary outcome). Secondary outcome was defined by a reduction of >50% in a Behavioral Avoidance Test (BAT). Mean within-session fear reduction functioned as a process measure for exposure. Compared to non-responders and pre-treatment, results in the discovery sample seemed to indicate that responders exhibited stronger negative connectivity between frontal and limbic structures and were characterized by heightened connectivity between the amygdala and ventral visual pathway regions. Patients exhibiting high within-session fear reduction showed stronger excitatory connectivity within the prefrontal cortex than patients with low within-session fear reduction. Whereas these results could be replicated by another team using the same data (cross-team replication), cross-site replication of the discovery sample findings in the independent replication sample was unsuccessful. Results seem to support negative fronto-limbic connectivity as promising ingredient to enhance response rates in specific phobia but lack sufficient replication. Further research is needed to obtain a valid basis for clinical decision-making and the development of individually tailored treatment options. Notably, future studies should regularly include replication approaches in their protocols.

Claudin-4 modulates autophagy via SLC1A5/LAT1 as a tolerance mechanism for genomic instability in ovarian cancer.

Genome instability is key for tumor heterogeneity and derives from defects in cell division and DNA damage repair. Tumors show tolerance for this characteristic, but its accumulation is regulated somehow to avoid catastrophic chromosomal alterations and cell death. Claudin-4 is upregulated and closely associated with genome instability and worse patient outcome in ovarian cancer. This protein is commonly described as a junctional protein participating in processes such as cell proliferation and DNA repair. However, its biological association with genomic instability is still poorly-understood. Here, we used CRISPRi and a claudin mimic peptide (CMP) to modulate the cladudin-4 expression and its function, respectively in in-vitro (high-grade serous carcinoma cells) and in-vivo (patient-derived xenograft in a humanized-mice model) systems. We found that claudin-4 promotes a protective cellular-mechanism that links cell-cell junctions to genome integrity. Disruption of this axis leads to irregular cellular connections and cell cycle that results in chromosomal alterations, a phenomenon associated with a novel functional link between claudin-4 and SLC1A5/LAT1 in regulating autophagy. Consequently, claudin-4's disruption increased autophagy and associated with engulfment of cytoplasm-localized DNA. Furthermore, the claudin-4/SLC1A5/LAT1 biological axis correlates with decrease ovarian cancer patient survival and targeting claudin-4 in-vivo with CMP resulted in increased niraparib (PARPi) efficacy, correlating with increased tumoral infiltration of T CD8+ lymphocytes. Our results show that the upregulation of claudin-4 enables a mechanism that promotes tolerance to genomic instability and immune evasion in ovarian cancer; thus, suggesting the potential of claudin-4 as a translational target for enhancing ovarian cancer treatment.

WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers.

Wnt ligand WNT4 is critical in female reproductive tissue development, with WNT4 dysregulation linked to related pathologies including breast cancer (invasive lobular carcinoma, ILC) and gynecologic cancers. WNT4 signaling in these contexts is distinct from canonical Wnt signaling yet inadequately understood. We previously identified atypical intracellular activity of WNT4 (independent of Wnt secretion) regulating mitochondrial function, and herein examine intracellular functions of WNT4. We further examine how convergent mechanisms of WNT4 dysregulation impact cancer metabolism. In ILC, WNT4 is co-opted by estrogen receptor α (ER) via genomic binding in WNT4 intron 1, while in gynecologic cancers, a common genetic polymorphism (rs3820282) at this ER binding site alters WNT4 regulation. Using proximity biotinylation (BioID), we show canonical Wnt ligand WNT3A is trafficked for secretion, but WNT4 is localized to the cytosol and mitochondria. We identified DHRS2, mTOR, and STAT1 as putative WNT4 cytosolic/mitochondrial signaling partners. Whole metabolite profiling, and integrated transcriptomic data, support that WNT4 mediates metabolic reprogramming via fatty acid and amino acid metabolism. Furthermore, ovarian cancer cell lines with rs3820282 variant genotype are WNT4 dependent and have active WNT4 metabolic signaling. In protein array analyses of a cohort of 103 human gynecologic tumors enriched for patient diversity, germline rs3820282 genotype is associated with metabolic remodeling. Variant genotype tumors show increased AMPK activation and downstream signaling, with the highest AMPK signaling activity in variant genotype tumors from non-White patients. Taken together, atypical intracellular WNT4 signaling, in part via genetic dysregulation, regulates the distinct metabolic phenotypes of ILC and gynecologic cancers. SIGNIFICANCE: WNT4 regulates breast and gynecologic cancer metabolism via a previously unappreciated intracellular signaling mechanism at the mitochondria, with WNT4 mediating metabolic remodeling. Understanding WNT4 dysregulation by estrogen and genetic polymorphism offers new opportunities for defining tumor biology, precision therapeutics, and personalized cancer risk assessment.

Converging Periodic Boundary Conditions and Detection of Topological Gaps on Regular Hyperbolic Tessellations.

Tessellations of the hyperbolic spaces by regular polygons support discrete quantum and classical models with unique spectral and topological characteristics. Resolving the true bulk spectra and the thermodynamic response functions of these models requires converging periodic boundary conditions and our Letter delivers a practical and rigorous solution for this open problem on generic {p,q}-tessellations. This enables us to identify the true spectral gaps of bulk Hamiltonians and construct all but one topological models that deliver the topological gaps predicted by the K theory of the lattices. We demonstrate the emergence of the expected topological spectral flows whenever two such bulk models are deformed into each other and prove the emergence of topological channels whenever a soft physical interface is created between different topological classes of Hamiltonians.

Influence of bone density on stability in TBW.

Osteoporosis is a common disease that leads to a reduction in bone density and increases the risk of fractures. Stable surgical treatment is particularly important for these fractures. The aim of this study was to examine the influence of bone density in the area of ​​the proximal ulna on the failure of the fixation technique of K-wires in tension band wiring (TBW). We provided 10 ulna specimens with TBW and biomechanically examined the pull-out strength of bi- and tricortical K-wires. Bone density measurement was performed using qCT. In the paired t-test, the tricortical group showed a significantly higher pull-out strength in relation to bone density than the bicortical group (p = 0.001). Furthermore, the Pearson correlation showed a high influence of bone density on pull-out strength in the tricortical group (r = 0.544), but without significance (p = 0.100).Our work shows that bone density has a direct effect on the pull-out strength of K-wires in TBW. TBW should therefore be used as osteosynthesis technique, especially in young patients with non-osteoporotic bones. In the case of osteoporotic fractures, alternative procedures should be preferred.

Mechanisms of action underlying virtual reality exposure treatment in spider phobia: Pivotal role of within-session fear reduction.

Although virtual-reality exposure treatment (VRET) for anxiety disorders is an efficient treatment option for specific phobia, mechanisms of action for immediate and sustained treatment response need to be elucidated. Towards this aim, core therapy process variables were assessed as predictors for short- and long-term VR treatment outcomes. In a bi-centric study, n = 186 patients with spider phobia completed a baseline-assessment, a one-session VRET, a post-therapy assessment, and a 6-month-follow-up assessment (ClinicalTrials.gov, ID: NCT03208400). Short- and long-term outcomes regarding self-reported symptoms in the spider phobia questionnaire (SPQ) and final patient-spider distance in the behavioral avoidance test (BAT) were predicted via logistic regression models with the corresponding baseline score, age, initial fear activation, within-session fear reduction and fear expectancy violation as predictors. To predict long-term remission status at 6-month-follow-up, dimensional short-term changes in the SPQ and BAT were additionally included. Higher within-session fear reductions predicted better treatment outcomes (long-term SPQ; short- and long-term BAT). Lower initial fear activation tended to be associated with better long-term outcomes (SPQ), while fear expectancy violation was not associated with any outcome measure. Short-term change in the SPQ predicted remission status. Findings highlight that in VRET for spider phobia, the experience of fear reduction is central for short- and long-term treatment success and should be focused by therapists.

Fast Twist Angle Mapping of Bilayer Graphene Using Spectroscopic Ellipsometric Contrast Microscopy.

Twisted bilayer graphene provides an ideal solid-state model to explore correlated material properties and opportunities for a variety of optoelectronic applications, but reliable, fast characterization of the twist angle remains a challenge. Here we introduce spectroscopic ellipsometric contrast microscopy (SECM) as a tool for mapping twist angle disorder in optically resonant twisted bilayer graphene. We optimize the ellipsometric angles to enhance the image contrast based on measured and calculated reflection coefficients of incident light. The optical resonances associated with van Hove singularities correlate well to Raman and angle-resolved photoelectron emission spectroscopy, confirming the accuracy of SECM. The results highlight the advantages of SECM, which proves to be a fast, nondestructive method for characterization of twisted bilayer graphene over large areas, unlocking process, material, and device screening and cross-correlative measurement potential for bilayer and multilayer materials.

Endoleak Detection after Endovascular Aortic Repair via Coded-Excitation Ultrasound-A Feasibility Study.

Endoleaks are the most common complication after endovascular aortic repair (EVAR). Their correct identification is one of the main objectives of surveillance protocols after EVAR. So far, computed tomography angiography (CTA), contrast-enhanced (CEUS) and Duplex ultrasound (DUS), as well as magnetic resonance angiography, have been investigated for their ability to detect endoleaks. In general, all technologies have distinct benefits and disadvantages, with CTA and CEUS emerging as the reference standard for surveillance after EVAR. However, they are both contrast-enhancer-dependent, and CTA additionally exposes patients to ionizing radiation. In the present study, we investigated B-Flow, a type of coded-excitation ultrasound that was specifically designed to optimize the visualization of blood flow, for its ability to detect endoleaks, and compared its performance to CEUS, CTA, and DUS. In total, 34 patients were included in the analysis that accumulated in 43 distinct B-Flow investigations. They underwent a total of 132 imaging investigations. Agreement between B-Flow and other imaging modalities was high (>80.0%), while inter-method reliability can be interpreted as good. However, with B-Flow, six and one endoleaks would have been missed compared to CEUS and CTA, respectively. Regarding endoleak classification, all metrics were lower but retained an adequate level of comparison. In a subset of patients requiring intervention, B-Flow had 100% accuracy regarding both endoleak detection and classification. Ultrasonography enables endoleak detection and classification without the need for pharmaceutical contrast enhancement or radiation. Ultrasound coded-excitation imaging in the application of B-Flow could further simplify surveillance after EVAR by offering adequate accuracy without requiring intravenous contrast enhancement. Our findings may promote subsequent investigations of coded-excitation imaging for endoleak detection and classification in the surveillance after EVAR.

In colon cancer cells fascin1 regulates adherens junction remodeling.

Adherens junctions (AJs) are a defining feature of all epithelial cells. They regulate epithelial tissue architecture and integrity, and their dysregulation is a key step in tumor metastasis. AJ remodeling is crucial for cancer progression, and it plays a key role in tumor cell survival, growth, and dissemination. Few studies have examined AJ remodeling in cancer cells consequently, it remains poorly understood and unleveraged in the treatment of metastatic carcinomas. Fascin1 is an actin-bundling protein that is absent from the normal epithelium but its expression in colon cancer is linked to metastasis and increased mortality. Here, we provide the molecular mechanism of AJ remodeling in colon cancer cells and identify for the first time, fascin1's function in AJ remodeling. We show that in colon cancer cells fascin1 remodels junctional actin and actomyosin contractility which makes AJs less stable but more dynamic. By remodeling AJs fascin1 drives mechanoactivation of WNT/ß-catenin signaling and generates "collective plasticity" which influences the behavior of cells during cell migration. The impact of mechanical inputs on WNT/ß-catenin activation in cancer cells remains poorly understood. Our findings highlight the role of AJ remodeling and mechanosensitive WNT/ß-catenin signaling in the growth and dissemination of colorectal carcinomas.

Parental Mental Illness, Borderline Personality Disorder, and Parenting Behavior: The Moderating Role of Social Support.

PURPOSE OF REVIEW: Parental mental disorders, particularly borderline personality disorder (BPD), impair parenting behavior. Consequently, the children exhibit an elevated risk for psychopathology across their lifespan. Social support for parents is thought to moderate the relationship between parental mental illness and parenting behavior. It may dampen negative effects and serve as starting point for preventive interventions. This paper provides a literature overview regarding the impact of social support on the sequelae of parental mental illness and BPD for parenting behavior. RECENT FINDINGS: Current literature highlights the increased burden of families with a mentally ill parent and associated changes in parenting behavior like increased hostility and affective dysregulation, especially in the context of parental BPD. Literature further demonstrates the powerful impact of social support in buffering such negative outcomes. The effect of social support seems to be moderated itself by further factors like socioeconomic status, gender, or characteristics of the social network. Social support facilitates positive parenting in mentally ill parents and may be particularly important in parents with BPD. However, social support is embedded within a framework of influencing factors, which need consideration when interpreting scientific results.

Noncollinear Spin Current for Switching of Chiral Magnetic Textures.

We propose a concept of noncollinear spin current, whose spin polarization varies in space even in nonmagnetic crystals. While it is commonly assumed that the spin polarization of the spin Hall current is uniform, asymmetric local crystal potential generally allows the spin polarization to be noncollinear in space. Based on microscopic considerations, we demonstrate that such noncollinear spin Hall currents can be observed, for example, in layered Kagome Mn_{3}X (X=Ge, Sn) compounds. Moreover, by referring to atomistic spin dynamics simulations we show that noncollinear spin currents can be used to switch the chiral spin texture of Mn_{3}X in a deterministic way even in the absence of an external magnetic field. Our theoretical prediction can be readily tested in experiments, which will open a novel route toward electric control of complex spin structures in noncollinear antiferromagnets.

Impact of Electric Field Disorder on Broken-Symmetry States in Ultraclean Bilayer Graphene.

Bilayer graphene (BLG) has multiple internal degrees of freedom and a constant density of states down to the charge neutrality point when trigonal warping is ignored. Consequently, it is susceptible to various competing ground states. However, a coherent experimental determination of the ground state has been challenging due to the interaction-disorder interplay. Here we present an extensive transport study in a series of dually gated freestanding BLG devices and identify the layer-antiferromagnet as the ground state with a continuous strength across all devices. This strength correlates with the width of the state in the electric field. We systematically identify electric-field disorder─spatial variations in the interlayer potential difference─as the main source responsible for the observations. Our results pinpoint for the first time the importance of electric-field disorder on spontaneous symmetry breaking in BLG and solve a long-standing debate on its ground state. The electric-field disorder should be universal to all 2D materials.

Quantum cascade of correlated phases in trigonally warped bilayer graphene.

Divergent density of states offers an opportunity to explore a wide variety of correlated electron physics. In the thinnest limit, this has been predicted and verified in the ultraflat bands of magic-angle twisted bilayer graphene1-5, the band touching points of few-layer rhombohedral graphite6-8 and the lightly doped rhombohedral trilayer graphene9-11. The simpler and seemingly better understood Bernal bilayer graphene is also susceptible to orbital magnetism at charge neutrality7 leading to layer antiferromagnetic states12 or quantum anomalous Hall states13. Here we report the observation of a cascade of correlated phases in the vicinity of electric-field-controlled Lifshitz transitions14,15 and van Hove singularities16 in Bernal bilayer graphene. We provide evidence for the observation of Stoner ferromagnets in the form of half and quarter metals10,11. Furthermore, we identify signatures consistent with a topologically non-trivial Wigner-Hall crystal17 at zero magnetic field and its transition to a trivial Wigner crystal, as well as two correlated metals whose behaviour deviates from that of standard Fermi liquids. Our results in this reproducible, tunable, simple system open up new horizons for studying strongly correlated electrons.