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Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche
Full text linkBone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we report that histone methyltransferase ASH1L is genetically amplified and is required for bone metastasis in men with prostate cancer. ASH1L rewires histone methylations and cooperates with HIF-1α to induce pro-metastatic transcriptome in invading cancer cells, resulting in monocyte differentiation into lipid-associated macrophage (LA-TAM) and enhancing their pro-tumoral phenotype in the metastatic bone niche. We identified IGF-2 as a direct target of ASH1L/HIF-1α and mediates LA-TAMs\u27 differentiation and phenotypic changes by reprogramming oxidative phosphorylation. Pharmacologic inhibition of the ASH1L-HIF-1α-macrophages axis elicits robust anti-metastasis responses in preclinical models. Our study demonstrates epigenetic alterations in cancer cells reprogram metabolism and features of myeloid components, facilitating metastatic outgrowth. It establishes ASH1L as an epigenetic driver priming metastasis and macrophage plasticity in the bone niche, providing a bona fide therapeutic target in metastatic malignancies
Gene Promoters Are Genomically Encoded To Facilitate Histone Exchange/Incorporation
Full text linkGene promoters are intrinsically hardwired not only to facilitate transcription preinitiation complex formation but also the release of paused RNA polymerase by H2A.Z. A new PLOS Biology study reveals poly (dA) tracts at promoters positively stimulate H2A.Z incorporation by the SWR complex in yeast
Rod Photoreceptor Regeneration in a Zebrafish Model with Retinitis Pigmentosa
No full textA cellular hallmark of inherited retinal degenerative diseases is progressive loss of photoreceptors until one is completely blind. Unlike mammalian models, Zebrafish have the ability to naturally regenerate their neurons after injury or disease is detected. We have generated a zebrafish model with the most common autosomal dominant form of the inherited retinal degenerative disease known as Retinitis Pigmentosa. We utilize immunohistochemistry, single-cell RNA sequencing, several analysis tools, behavioral assays and oligonucleotides to characterize our zebrafish model and identify the transcription factors necessary for rod photoreceptor regeneration. We show that our zebrafish model has continuous degeneration and regeneration of rod photoreceptors throughout its entire life, maintains a retinal environment characteristic of early stages of Retinitis Pigmentosa, and has behavioral deficits caused by the loss of rods. Finally, we identify and validate genes that play an important role in the proliferation of progenitor cells, differentiation of progenitor cells into rod photoreceptors, maturation, and integration of these rod photoreceptors. Future studies will continue to investigate the mechanism by which newly formed rods are able to integrate into the retina. These findings will be vital for therapeutic strategies trying to restore vision to the blind
Antitumor Activity and Biomarker Analysis for TROP2 Antibody-Drug Conjugate Datopotamab Deruxtecan in Patient-Derived Breast Cancer Xenograft Models
Full text linkPURPOSE: Datopotamab deruxtecan (Dato-DXd) is a humanized anti-trophoblast cell-surface antigen-2 (TROP2) IgG1 mAb linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCX) varying in TROP2 expression.
EXPERIMENTAL DESIGN: The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors postneoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 expression on Dato-DXd activity was assessed in vitro and in vivo using viral overexpression in BCX-derived cell lines.
RESULTS: Models differed in their sensitivity to both Dato-DXd and IgG-DXd. Dato-DXd (10 mg/kg) led to objective response in 4 (36%) models and statistically significant prolongation of event-free survival in 8 (73%) models, whereas IgG-DXd (10 mg/kg) led to response in 1 (9%) and prolonged event-free survival in 3 (27%) models. TROP2 RNA and protein were significantly higher in Dato-DXd-sensitive models. In isogenic cell lines derived from Dato-DXd-resistant BCXs, overexpression of TROP2 conferred Dato-DXd antitumor activity in vitro and in vivo. Dato-DXd increased γH2AX and phospho-KAP1 in the two Dato-DXd-sensitive BCXs but not in a Dato-DXd-resistant BCX. In Dato-DXd-sensitive models, antitumor activity was enhanced in combination with a PARP inhibitor, olaparib.
CONCLUSIONS: Dato-DXd is active in breast cancer models. Dato-DXd has TROP2-dependent and -independent mediators of activity; however, high TROP2 expression enhances Dato-DXd antitumor activity
Cell Cycle Progression of Under-Replicated Cells
Full text linkCell cycle checkpoints are the regulatory mechanisms that secure the strict order of cellular events for cell division that ensure genome integrity. It has been proposed that mitosis initiation depends on the completion of DNA replication, which must be tightly controlled to guarantee genome duplication. Contrary to these conventional hypotheses, we showed here that cells were able to enter mitosis without completion of DNA replication. Although DNA replication was not completed in cells upon depletion of MCM2, CDC45 or GINS4, these under-replicated cells progressed into mitosis, which led to cell death. These unexpected results challenge current model and suggest the absence of a cell cycle checkpoint that monitors the completion of DNA replication
Navigating Nonlinear Pathways: Challenges and Opportunities for Diversity, Equity, and Inclusion Leaders in Academic Emergency Medicine
Full text linkOBJECTIVES: Diversity, equity, and inclusion (DEI) leadership roles have grown in academic emergency medicine (EM). We sought to elucidate specific pathways to DEI leadership roles among current DEI leaders in academic EM.
METHODS: From March to May 2023, we conducted semistructured, qualitative interviews with DEI leaders in academic EM across 5 US regions to investigate their pathways to leadership. Participants were recruited via email using Accreditation Council for Graduate Medical Education-accredited EM residency websites and the Academy for Diversity and Inclusion in EM. After recording and transcribing the interviews, we used an inductive approach to identify major themes.
RESULTS: Of 56 DEI leaders contacted, 25 agreed to participate, and 21 were interviewed. The median (range) interview duration was 34 (25-63) minutes. Leadership titles included directors, chairs, vice chairs, committee chairs, chiefs, advisors, and deans. Three major themes emerged: (1) nonlinear pathways-participants reached DEI roles through informal assumption, volunteering, or self-creation, often without initial aspiration or compensation; (2) undefined roles and expectations-roles and responsibilities were often determined by leaders themselves, with advantages and disadvantages; (3) variable perceived value in promotions-participants felt DEI efforts were frequently undervalued in academic promotion, with mentorship highlighted as crucial for translating DEI activities into academic achievements.
CONCLUSION: Our study provides important insights not only into the pathways to DEI leadership among current leaders in academic EM but also into the challenges and opportunities DEI leaders perceive when navigating roles, responsibilities, and academic promotion
Factors Driving Adolescent Tuberculosis Incidence by Age and Sex in 30 High-Tuberculosis Burden Countries: A Mathematical Modelling Study
Full text linkINTRODUCTION: During adolescence, tuberculosis incidence rises, with a greater increase in males compared with females. Tuberculosis notifications and estimates infrequently disaggregate adolescent age groups. Moreover, the factors that drive the increases in overall incidence and the male-to-female (MF) ratio remain unclear.
METHODS: We constructed a mechanistic model to estimate cumulative Mycobacterium tuberculosis infection and tuberculosis disease incidence in the WHO’s 30 high-tuberculosis burden countries (HBCs), which represent 86%–90% of global tuberculosis incidence. We derived infection risk from tuberculosis prevalence and assortative social mixing based on sex and age (10–14 years vs 15–19 years old). We adjusted age subgroup-specific risks of disease progression by age- and sex-specific risks of low body mass index (BMI), pregnancy and postpartum period (PPP) and HIV coinfection. We calculated population attributable fractions (PAFs) to these factors.
RESULTS: In 2019, 91.2 million (95% uncertainty interval (UI) 83.9 to 99.3 million) adolescents in the 30 HBCs had been infected with M. tuberculosis, and an estimated 1.0 million (95% UI 0.8 to 1.2 million) developed tuberculosis disease. The median PAF of tuberculosis disease to HIV, modified by antiretroviral therapy, was 1% and highest in Southern Africa. The median PAF for PPP among older adolescents of both sexes was 2.6%. The median PAF to low BMI was 16% and highest in South Asia. The MF risk ratio of tuberculosis disease was 1.2-fold higher among older adolescents, relative to young adolescents. The widening MF risk ratio was attributable mostly to low BMI, with a smaller contribution from sex-assortative social mixing.
CONCLUSION:Globally, large numbers of adolescents have been infected by M. tuberculosis and develop tuberculosis disease. Low BMI is the most important contributor to the overall incidence of tuberculosis disease, as well as to the sex difference that widens with age
Diverse Ancestral Representation Improves Genetic Intolerance Metrics
No full textThe unprecedented scale of genomic databases has revolutionized our ability to identify regions in the human genome intolerant to variation—regions often implicated in disease. However, these datasets remain constrained by limited ancestral diversity. Here, we analyze whole-exome sequencing data from 460,551 UK Biobank and 125,748 Genome Aggregation Database (gnomAD) participants across multiple ancestries to test several key intolerance metrics, including the Residual Variance Intolerance Score (RVIS), Missense Tolerance Ratio (MTR), and Loss-of-Function Observed/Expected ratio (LOF O/E). We demonstrate that increasing ancestral representation, rather than sample size alone, critically drives their performance. Scores trained on variation observed in African and Admixed American ancestral groups show higher resolution in detecting haploinsufficient and neurodevelopmental disease risk genes compared to scores trained on European ancestry groups. Most strikingly, MTR trained on 43,000 multi-ancestry exomes demonstrates greater predictive power than when trained on a nearly 10-fold larger dataset of 440,000 non-Finnish European exomes. We further find that European ancestry group-based scores are likely approaching saturation. These findings highlight the need for enhanced population representation in genomic resources to fully realize the potential of precision medicine and drug discovery. Ancestry group-specific scores are publicly available through an interactive portal: http://intolerance.public.cgr.astrazeneca.com
The Multilayered Control of Acetylation During Adenovirus-Based Immunotherapy of Cancer
No full textAdenoviruses are highly immunogenic agents that have shown promise first as gene delivery vectors and later as oncolytic viruses. Currently, oncolytic adenoviruses are featured in over 30% of cancer virotherapy clinical trials. Due to their effective cellular uptake and hijack of cellular machinery, replication-competent adenoviruses are promising therapeutic agents for treating a wide range of tumors. Adenoviral influence on host cell acetylome regulation has regained attention, as these viruses redirect or suppress acetylation during replication, making them potentially desirable therapeutic agents for cancers driven by epigenetic modifications. In this review, we aim to cover the viral processes influencing the acetylome of the host genome. In addition, we shall discuss the effect of differential acetylation on the antiviral defense mounted by the host immune system. Lastly, we will discuss the opportunities for combining acetylation modifiers with oncolytic adenoviruses to improve further outcomes for patients treated with viroimmunotherapy
Three-Dimensional Deep Learning Normal Tissue Complication Probability Model to Predict Late Xerostomia in Patients With Head and Neck Cancer
Full text linkPurpose: Conventional normal tissue complication probability (NTCP) models for patients with head and neck cancer are typically based on single-value variables, which, for radiation-induced xerostomia, are baseline xerostomia and mean salivary gland doses. This study aimed to improve the prediction of late xerostomia by using 3-dimensional information from radiation dose distributions, computed tomography imaging, organ-at-risk segmentations, and clinical variables with deep learning (DL).
Methods and materials: An international cohort of 1208 patients with head and neck cancer from 2 institutes was used to train and twice validate DL models (deep convolutional neural network, EfficientNet-v2, and ResNet) with 3-dimensional dose distribution, computed tomography scan, organ-at-risk segmentations, baseline xerostomia score, sex, and age as input. The NTCP endpoint was moderate-to-severe xerostomia 12 months postradiation therapy. The DL models\u27 prediction performance was compared with a reference model: a recently published xerostomia NTCP model that used baseline xerostomia score and mean salivary gland doses as input. Attention maps were created to visualize the focus regions of the DL predictions. Transfer learning was conducted to improve the DL model performance on the external validation set.
Results: All DL-based NTCP models showed better performance (area under the receiver operating characteristic curve [AUC]test, 0.78-0.79) than the reference NTCP model (AUCtest, 0.74) in the independent test. Attention maps showed that the DL model focused on the major salivary glands, particularly the stem cell-rich region of the parotid glands. DL models obtained lower external validation performance (AUCexternal, 0.63) than the reference model (AUCexternal, 0.66). After transfer learning on a small external subset, the DL model (AUCtl, external, 0.66) performed better than the reference model (AUCtl, external, 0.64).
Conclusion: DL-based NTCP models performed better than the reference model when validated in data from the same institute. Improved performance in the external data set was achieved with transfer learning, demonstrating the need for multicenter training data to realize generalizable DL-based NTCP models