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Scholars within the fields of public health, health education, health promotion, and health communication look to specific theories to explain health behavior change. The purpose of this article is to critically compare four health theories and key variables within them with regard to behavior change in the area of reproductive health. Using cross-country analyses of Ghana, Nepal, and Nicaragua (data sets provided by the Center for Communication Programs, Johns Hopkins University), the authors looked at the Health Belief Model, Theory of Reasoned Action, Extended Parallel Process Model, and Social Cognitive Theory for these two defined objectives. Results show that all four theories provide an excellent fit to the data, but that certain variables within them may have particular value for understanding specific aspects of behavior change. Recommendations for the selection of theories to use as guidelines in the design and evaluation of reproductive health programs are provided. [ABSTRACT FROM AUTHOR]

C/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBPγ is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBPα hypermethylation/silencing. Similarly, C/EBPγ was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBPα, as C/EBPα mediates C/EBPγ suppression. Studies in myeloid cells demonstrated that CEBPG overexpression blocked neutrophilic differentiation. Further, downregulation of Cebpg in murine Cebpa-deficient stem/progenitor cells or in human CEBPA-silenced AML samples restored granulocytic differentiation. In addition, treatment of these leukemias with demethylating agents restored the C/EBPα-C/EBPγ balance and upregulated the expression of myeloid differentiation markers. Our results indicate that C/EBPγ mediates the myeloid differentiation arrest induced by C/EBPα deficiency and that targeting the C/EBPα-C/EBPγ axis rescues neutrophilic differentiation in this unique subset of AMLs. [ABSTRACT FROM AUTHOR]

Viral mimicry refers to the activation of innate anti-viral immune responses due to the induction of endogenous retroelement (RE) expression. Viral mimicry has been previously described to augment anti-tumor immune responses and sensitize solid tumors to immunotherapy including colorectal cancer, melanoma, and clear renal cell carcinoma. Here, we found that targeting a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI). ZNF638 recruits the HUSH complex, which precipitates repressive H3K9me3 marks on endogenous REs. In GBM, ZNF638 is associated with marked locoregional immunosuppressive transcriptional signatures, reduced endogenous RE expression and poor immune cell infiltration (CD8 + T-cells, dendritic cells). ZNF638 knockdown decreased H3K9-trimethylation, increased cytosolic dsRNA and activated intracellular dsRNA-signaling cascades (RIG-I, MDA5 and IRF3). Furthermore, ZNF638 knockdown upregulated antiviral immune programs and significantly increased PD-L1 immune checkpoint expression in patient-derived GBM neurospheres and diverse murine models. Importantly, targeting ZNF638 sensitized mice to ICI in syngeneic murine orthotopic models through innate interferon signaling. This response was recapitulated in recurrent GBM (rGBM) samples with radiographic responses to checkpoint inhibition with widely increased expression of dsRNA, PD-L1 and perivascular CD8 cell infiltration, suggesting dsRNA-signaling may mediate response to immunotherapy. Finally, we showed that low ZNF638 expression was a biomarker of clinical response to ICI and improved survival in rGBM patients and melanoma patients. Our findings suggest that ZNF638 could serve as a target to potentiate immunotherapy in gliomas.

Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of biologically distinct entities characterized by variable degrees of ineffective hematopoiesis. Recently, 2 classification systems (the 5th edition of the World Health Organization Classification of Haematolymphoid tTumours and the International Consensus Classification) further subcharacterized MDS into morphologically and genetically defined groups. Accurate diagnosis and subclassification of MDS require a multistep systemic approach. The International Consortium for MDS (icMDS) summarizes a contemporary, practical, and multimodal approach to MDS diagnosis and classification., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: We aim to determine whether incremental changes in genetic ancestry percentages influence molecular and clinical outcome characteristics of breast cancer in an admixed population., Background: Patients with breast cancer are predominantly characterized as "Black" or "White" based on self-identified race/ethnicity or arbitrary genetic ancestry cutoffs. This limits scientific discovery in populations that are admixed or of mixed race/ethnicity as they cannot be classified based on historical race/ethnicity boxes or genetic ancestry cutoffs., Methods: We used The Cancer Genome Atlas cohort and focused on genetically admixed patients that had less than 90% European, African, Asian, or Native American ancestry., Results: Genetically admixed patients with breast cancer exhibited improved 10-year overall survival relative to those with >90% European ancestry. Within the luminal A subtype, patients with lower African ancestry had longer 10-year overall survival compared to those with higher African ancestry. The correlation of genetic ancestry with gene expression and DNA methylation in the admixed cohort revealed novel ancestry-specific intrinsic PAM50 subtype patterns. In luminal A tumors, genetic ancestry was correlated with both the expression and methylation of signaling genes, while in basal-like tumors, genetic ancestry was correlated with stemness genes. In addition, we took a machine-learning approach to estimate genetic ancestry from gene expression or DNA methylation and were able to accurately calculate ancestry values from a reduced set of 10 genes or 50 methylation sites that were specific for each molecular subtype., Conclusions: Our results suggest that incremental changes in genetic ancestry percentages result in ancestry-specific molecular differences even between well-established PAM50 subtypes which may influence disparities in breast cancer survival outcomes. Accounting for incremental changes in ancestry will be important in future research, prognostication, and risk stratification, particularly in ancestrally diverse populations., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In Malawi, various brands of the COVID-19 vaccine have been offered to the population, but factors including fear of side effects or other risks, uncertainty about benefits, and misinformation created hesitancy toward them. In early 2022, 4% of Malawians were fully vaccinated for COVID-19. Despite multiple promotion efforts, by August 2022, COVID-19 vaccination nationwide was around 15%. To increase COVID-19 vaccination uptake, the research team collected qualitative data in 4 districts with vaccine coverage levels ranging from 1% to 11%. This data collection happened during a cholera outbreak that began in March 2022 and the vaccination efforts to address it. Study participants included male and female members of the general population, social workers, people with comorbidities, health workers, and community leaders (224 participants total, 47% female). In focus group discussions (n=27) and in-depth interviews (n=17), participants compared COVID-19 vaccines with other adult vaccines, such as cholera and tetanus toxoid. A thematic analysis identified themes related to 3 research questions on COVID-19 vaccine concerns, confidence, and delivery affecting uptake. Differences in promotion, delivery (oral versus injection), COVID-19 vaccine card structure, the various brands and boosters, and vaccines being described as required or optional all played a role in distinguishing COVID-19 vaccines from other vaccines and creating suspicion or indifference. Barriers to vaccination in general, such as rumors or knowledge gaps, were amplified by how novel the COVID-19 vaccines were perceived to be and the changing guidance provided over time. By April 2023, more targeted campaign efforts helped increase vaccination rates to 28%. The findings contribute information about how individuals conceptualize and make decisions about adult vaccination, which can, in turn, inform strategies to integrate COVID-19 promotion and delivery with other disease responses in Malawi as well as routine health services in similar settings., (© Tibbels et al.)

The guidelines for classification, prognostication, and response assessment of myelodysplastic syndromes/neoplasms (MDS) have all recently been updated. In this report on behalf of the International Consortium for MDS (icMDS) we summarize these developments. We first critically examine the updated World Health Organization (WHO) classification and the International Consensus Classification (ICC) of MDS. We then compare traditional and molecularly based risk MDS risk assessment tools. Lastly, we discuss limitations of criteria in measuring therapeutic benefit and highlight how the International Working Group (IWG) 2018 and 2023 response criteria addressed these deficiencies and are endorsed by the icMDS. We also address the importance of patient centered care by discussing the value of quality-of-life assessment. We hope that the reader of this review will have a better understanding of how to classify MDS, predict clinical outcomes and evaluate therapeutic outcomes., Competing Interests: Declaration of Competing Interest Maximilian Stahl consulted for Curis Oncology and Boston Consulting; served on the advisory board for Novartis and Kymera, GSK, Rigel, Sierra Oncology; and participated in GME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options (CCO). Elizabeth A. Griffiths has received honoraria for advisory board membership from AbbVie, Alexion Pharmaceuticals, Apellis, Celgene/BMS, CTI Biopharma, Genentech, Novartis, Picnic Health, Takeda Oncology, Taiho Oncology. EAG has received research funding from Astex Pharmaceuticals, AstraZeneca Rare Disease, Alexion Pharmaceuticals, Apellis Pharmaceuticals, Blueprint Medicines, Genentech Inc., and honoraria for CME activities from Physicians Educational Resource, MediComWorldwide, American Society of Hematology, AAMDS International Foundation. Ravindra Majeti is on the Advisory Boards of Kodikaz Therapeutic Solutions, Syros Pharmaceuticals, TenSixteen Bio, Roche, and Cullgen Inc. and is an inventor on several patents related to CD47 cancer immunotherapy licensed to Gilead Sciences. R.M. receives research support from Gilead Sciences. Ravindra Majeti. is a co-founder and equity holder of Pheast Therapeutics, MyeloGene, and Orbital Therapeutics. Stephanie Halene consulted for Forma Therapeutics. Daniel T. Starczynowski is a consultant and received research funding from Kymera Therapeutics, Kurome Therapeutics, Captor Therapeutics, and Tolero Therapeutics. Daniel T. Starczynowski has equity in Kurome Therapeutics. Gail Roboz: Consultancy: Abbvie, Amgen, Argenx, Astra Zeneca, Bluebird Bio, Blueprint Medicines, Bristol-Myers Squibb, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses Pharma, GlaxoSmithKline, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Novartis, Pfizer, Rigel, Roche, Syndax, Takeda (IRC Chair), Telix Pharma Research support: Janssen. David A. Sallman served on the advisory board of Aprea, AvenCell, BlueBird Bio, BMS, Intellia, Kite, Novartis, Shattuck Labs, Servier, Syndax. David A. Sallman served as a consultant for AbbVie, Magenta, Molecular Partners AG, Takeda and on the speakers' bureau for BMS, Incyte, Servier; David A. Sallman received research funding from Aprea, Jazz. Mrinal Patnaik received research funding from Kura Oncology and StemLine Pharmaceuticals. Andrew Brunner received consulting or advisory board honoraria from Novartis, Acceleron, Agios, Abbvie, Takeda, Celgene/BMS, Keros Therapeutics, Taiho, Gilead. Andrew Brunner has research support from the NIH SPORE in Myeloid Malignancies, and from the Edward P. Evans Foundation. Tae Kon Kim received research funding from Nextcure and is a consultant for Agenus. Alan List is employed by and has equity in Precision BioSciences, and has served as a consultant for Halia Therapeutics, CTI Biopharma, Aileron. Naval Daver has received research funding from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol-Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. Guillermo Sanz received honoraria, advisory board membership or consultation fees from AbbVie, BMS, ExCellThera, Novartis, Roche, and Takeda and participated in sponsored speaker's bureau for BMS, Novartis, and Takeda. Mikkael A. Sekeres has served on advisory boards for BMS, Novartis, Kurome, and Gilead. Pierre Fenaux received research funding from BMS, Abbvie, Jazz Pharmaceuticals, Novartis, and Janssen. Pierre Fenaux had a consultancy with and received honoraria from BMS, Abbvie, Jazz Pharmaceuticals, and Novartis. Fabio Efficace had a consultancy or advisory role for AbbVie, Incyte, Janssen, and Syros, outside the submitted work. Omar Abdel-Wahab has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder; Omar Abdel-Wahab has received prior research funding from H3B Biomedicine and LOXO Oncology unrelated to the current manuscript. Andrew H.Wei has served on advisory boards for Novartis, Astra Zeneca, Astellas, Janssen, Jazz, Amgen, Roche, Pfizer, Abbvie, Servier, Gilead, BMS, Shoreline, Macrogenics, Novartis and Agios; receives research funding to the Institution from Novartis, Abbvie, Servier, Janssen, BMS, Syndax, Astex, Astra Zeneca, Amgen; serves on speaker's bureaus for Abbvie, Novartis, BMS, Servier, Astellas; Andrew H.Wei is an employee of the Walter and Eliza Hall Institute (WEHI). WEHI receives milestone and royalty payments related to the development of Venetoclax. Current and past employees of Walter and Eliza Hall Institute may be eligible for financial benefits related to these payments. Andrew H. Wei receives such a financial benefit. Amer M. Zeidan received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron and Celgene/BMS. The National Heart, Lung, and Blood Institute receives research funding for the laboratory of Dr. Hourigan from Sellas and from the Foundation of the NIH AML MRD Biomarkers Consortium. All other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: The primary objective of this study was to evaluate the prescription patterns and appropriateness of the use of gastroprotectant medication in cats., Methods: Pharmacy dispensation logs from an academic tertiary referral center were reviewed between 1 January 2018 and 31 December 2018. Cats that were administered proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), sucralfate, misoprostol, antacids or a combination were included. Data regarding medication, dosage, formulation, duration of administration, completeness of discharge instructions and clinical rationales for administration were obtained from medical records. The appropriateness of gastroprotectant use was assessed according to the American College of Veterinary Internal Medicine consensus statement guidelines., Results: Of the 110 cases, 67 (60.9%) were prescribed a gastroprotectant medication without an appropriate indication. The most common reason for prescription was acute kidney injury in 26/67 (38.8%). PPIs were the most common gastroprotectant medication administered in 95/110 (86.3%) cats, followed by sucralfate in 18/110 (16.4%) and H2RAs in 11/110 (10%). Of the 35 cases in which gastroprotectant therapy was indicated, the medication chosen or dosage administered was considered suboptimal in 16 (45.7%). Instructions regarding the duration of administration, potential adverse effects and timing of administration in relation to meals or other medications were inconsistently provided in discharge instructions to pet owners. Of the 29 cases discharged with omeprazole, only 13 (44.8%) instructions included a duration of administration, while 6 (20.7%) recommended continuing gastroprotectants indefinitely until further notice, 16 (55.2%) discussed the timing of the administration in relation to a meal and six (20.7%) mentioned potential adverse effects; none advised tapering of omeprazole before discontinuation., Conclusions and Relevance: When prescribed, gastroprotectant medications were frequently prescribed injudiciously to cats in this referral population over a 12-month period. Discharge instructions to pet owners also often lacked information and recommendations regarding optimal administration, potential adverse effects, and tapering or discontinuation of the medications., Competing Interests: Conflict of interestThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Biological events that contribute to the pathogenesis of myelodysplastic syndromes/neoplasms (MDS) are becoming increasingly characterized and are being translated into rationally designed therapeutic strategies. Herein, we provide updates from the first International Workshop on MDS (iwMDS) of the International Consortium for MDS (icMDS) detailing recent advances in understanding the genetic landscape of MDS, including germline predisposition, epigenetic and immune dysregulation, the complexities of clonal hematopoiesis progression to MDS, as well as novel animal models of the disease. Connected to this progress is the development of novel therapies targeting specific molecular alterations, the innate immune system, and immune checkpoint inhibitors. While some of these agents have entered clinical trials (e.g., splicing modulators, IRAK1/4 inhibitors, anti-CD47 and anti-TIM3 antibodies, and cellular therapies), none have been approved for MDS. Additional preclinical and clinical work is needed to develop a truly individualized approach to the care of MDS patients., Competing Interests: Declaration of Competing Interest Maximilian Stahl consulted for Curis Oncology and Boston Consulting; served on the advisory board for Novartis and Kymera; and participated in GME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options (CCO). Elizabeth A. Griffiths has received honoraria for advisory board membership from AbbVie, Alexion Pharmaceuticals, Apellis, Celgene/BMS, CTI Biopharma, Genentech, Novartis, Picnic Health, Takeda Oncology, Taiho Oncology. EAG has received research funding from Astex Pharmaceuticals, AstraZeneca Rare Disease, Alexion Pharmaceuticals, Apellis Pharmaceuticals, Blueprint Medicines, Genentech Inc., and honoraria for CME activities from Physicians Educational Resource, MediComWorldwide, American Society of Hematology, AAMDS International Foundation. Ravindra Majeti is on the Advisory Boards of Kodikaz Therapeutic Solutions, Syros Pharmaceuticals, TenSixteen Bio, Roche, and Cullgen Inc. and is an inventor on a number of patents related to CD47 cancer immunotherapy licensed to Gilead Sciences. R.M. receives research support from Gilead Sciences. Ravindra Majeti. is a co-founder and equity holder of Pheast Therapeutics, MyeloGene, and Orbital Therapeutics. Stephanie Halene consulted for Forma Therapeutics. Daniel T. Starczynowski is a consultant and received research funding from Kymera Therapeutics, Kurome Therapeutics, Captor Therapeutics, and Tolero Therapeutics. Daniel T. Starczynowski has equity in Kurome Therapeutics. David A. Sallman served on the advisory board of Aprea, AvenCell, BlueBird Bio, BMS, Intellia, Kite, Novartis, Shattuck Labs, Servier, Syndax. David A. Sallman served as a consultant for AbbVie, Magenta, Molecular Partners AG, Takeda and on the speakers' bureau for BMS, Incyte, Servier; David A. Sallman received research funding from Aprea, Jazz. Mrinal Patnaik received research funding from Kura Oncology and StemLine Pharmaceuticals. Andrew Brunner received consulting or advisory board honoraria from Novartis, Acceleron, Agios, Abbvie, Takeda, Celgene/BMS, Keros Therapeutics, Taiho, Gilead. Andrew Brunner has research support from the NIH SPORE in Myeloid Malignancies, and from the Edward P. Evans Foundation. Tae Kon Kim received research funding from Nextcure and is a consultant for Agenus. Alan List is employed by and has equity in Precision BioSciences, and has served as a consultant for Halia Therapeutics, CTI Biopharma, Aileron. Naval Daver has received research funding from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol-Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. Guillermo Sanz received honoraria, advisory board membership or consultation fees from AbbVie, BMS, ExCellThera, Novartis, Roche, and Takeda and participated in sponsored speaker's bureau for BMS, Novartis, and Takeda. Mikkael A. Sekeres has served on advisory boards for BMS, Novartis, Kurome, and Gilead. Pierre Fenaux received research funding from BMS, Abbvie, Jazz Pharmaceuticals, Novartis, and Janssen. Pierre Fenaux had a consultancy with and received honoraria from BMS, Abbvie, Jazz Pharmaceuticals, and Novartis. Omar Abdel-Wahab has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder; Omar Abdel-Wahab has received prior research funding from H3B Biomedicine and LOXO Oncology unrelated to the current manuscript. Andrew H.Wei has served on advisory boards for Novartis, Astra Zeneca, Astellas, Janssen, Jazz, Amgen, Roche, Pfizer, Abbvie, Servier, Gilead, BMS, Shoreline, Macrogenics, Novartis and Agios; receives research funding to the Institution from Novartis, Abbvie, Servier, Janssen, BMS, Syndax, Astex, Astra Zeneca, Amgen; serves on speaker's bureaus for Abbvie, Novartis, BMS, Servier, Astellas; Andrew H.Wei is an employee of the Walter and Eliza Hall Institute (WEHI). WEHI receives milestone and royalty payments related to the development of Venetoclax. Current and past employees of Walter and Eliza Hall Institute may be eligible for financial benefits related to these payments. Andrew H.Wei receives such a financial benefit. Valeria Santini served in advisory boards from Abbvie, BMS, Geron, Gilead,Menarini, Novartis, Servier, Syros, ad received research support from BMS. Amer M. Zeidan received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron and Celgene/BMS. The National Heart, Lung, and Blood Institute receives research funding for the laboratory of Dr. Hourigan from Sellas and from the Foundation of the NIH AML MRD Biomarkers Consortium. All other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

There is growing interest in the consumption of halophytes due to their excellent nutritional profile and antioxidant properties, and their cultivation offers viable alternatives in the face of irreversible global salinization of soils. Nevertheless, abiotic factors strongly influence their phytochemical composition, and little is known about how growing conditions can produce plants with the best nutritional and functional properties. Crithmum maritimum is an edible halophyte with antioxidant properties and considerable potential for sustainable agriculture in marginal environments. However, it is found naturally in contrasting habitats with variable soil physicochemical properties and the extent to which edaphic factors can influence plant performance, accumulation of phytochemicals and their quality remains unknown. We investigated the influence of soil physicochemical properties (texture, pH, electrical conductivity, organic matter content and mineral element concentrations) on growth and reproductive performance, nutritional traits, and the accumulation of specific metabolites in C. maritimum. Soil, leaf and seed samples were taken from eight C. maritimum populations located on the southern coasts of Spain and Portugal. We found greater vegetative growth and seed production in coarser, sandier soils with lower microelement concentrations. The nutritional traits of leaves varied, with soil organic matter and macronutrient content associated with reduced leaf Na, protein and phenolic (mainly flavonoid) concentrations, whereas soils with lower pH and Fe concentrations, and higher clay content yielded plants with lower leaf Zn concentration and greater accumulation of hydroxycinnamic acids. The nutritional value of the seed oil composition appeared to be enhanced in soils with coarser texture and lower microelement concentrations. The accumulation of specific phenolic compounds in the seed was influenced by a wide range of soil properties including texture, pH and some microelements. These findings will inform the commercial cultivation of C. maritimum, particularly in the economic exploitation of poorly utilized, saline soils., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: Neighborhood-level disadvantage is an important factor in the creation and persistence of underresourced neighborhoods with an undue burden of disparate breast cancer-specific survival outcomes. Although studies have evaluated neighborhood-level disadvantage and breast cancer-specific survival after accounting for individual-level socioeconomic status (SES) in large national cancer databases, these studies are limited by age, socioeconomic, and racial and ethnic diversity., Objective: To investigate neighborhood SES (using a validated comprehensive composite measure) and breast cancer-specific survival in a majority-minority population., Design, Setting, and Participants: This retrospective multi-institutional cohort study included patients with stage I to IV breast cancer treated at a National Cancer Institute-designated cancer center and sister safety-net hospital from January 10, 2007, to September 9, 2016. Mean (SD) follow-up time was 60.3 (41.4) months. Data analysis was performed from March 2022 to March 2023., Exposures: Neighborhood SES was measured using the Area Deprivation Index (tertiles), a validated comprehensive composite measure of neighborhood SES., Main Outcomes and Measures: The primary outcome was breast cancer-specific survival. Random effects frailty models for breast cancer-specific survival were performed controlling for individual-level sociodemographic, comorbidity, breast cancer risk factor, access to care, tumor, and National Comprehensive Cancer Network guideline-concordant treatment characteristics. The Area Deprivation Index was calculated for each patient at the census block group level and categorized into tertiles (T1-T3)., Results: A total of 5027 women with breast cancer were included: 55.8% were Hispanic, 17.5% were non-Hispanic Black, and 27.0% were non-Hispanic White. Mean (SD) age was 55.5 (11.7) years. Women living in the most disadvantaged neighborhoods (T3) had shorter breast cancer-specific survival compared with those living in the most advantaged neighborhoods (T1) after controlling for individual-level sociodemographic, comorbidity, breast cancer risk factor, access to care, tumor, and National Comprehensive Cancer Network guideline-concordant treatment characteristics (T3 vs T1: hazard ratio, 1.29; 95% CI, 1.01-1.65; P < .04)., Conclusions and Relevance: In this cohort study, a shorter breast cancer-specific survival in women from disadvantaged neighborhoods compared with advantaged neighborhoods was identified, even after controlling for individual-level sociodemographic, comorbidity, breast cancer risk factor, access to care, tumor, and National Comprehensive Cancer Network guideline-concordant treatment characteristics. The findings suggest potential unaccounted mechanisms, including unmeasured social determinants of health and access to care measures. This study also lays the foundation for future research to evaluate whether social adversity from living in a disadvantaged neighborhood is associated with more aggressive tumor biologic factors, and ultimately shorter breast cancer-specific survival, through social genomic and/or epigenomic alterations.

TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

DNMT3A and IDH1/2 mutations combinatorically regulate the transcriptome and the epigenome in acute myeloid leukemia; yet the mechanisms of this interplay are unknown. Using a systems approach within topologically associating domains, we find that genes with significant expression-methylation correlations are enriched in signaling and metabolic pathways. The common denominator across these methylation-regulated genes is the density in MIR retrotransposons of their introns. Moreover, a discrete number of CpGs overlapping enhancers are responsible for regulating most of these genes. Established mouse models recapitulate the dependency of MIR-rich genes on the balanced expression of epigenetic modifiers, while projection of leukemic profiles onto normal hematopoiesis ones further consolidates the dependencies of methylation-regulated genes on MIRs. Collectively, MIR elements on genes and enhancers are susceptible to changes in DNA methylation activity and explain the cooperativity of proteins in this pathway in normal and malignant hematopoiesis., (© 2022. The Author(s).)

Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well-defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1-mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1 tumor-suppressive activity and identifies a therapeutic strategy in PRC1.1-mutated cancer., Significance: We demonstrate that BCOR and BCORL1 mutations in leukemia unlink PRC1.1 repressive function from target genes, resulting in epigenetic reprogramming and activation of aberrant cell signaling programs that mediate treatment resistance. Our study provides mechanistic insights into the pathogenesis of PRC1.1-mutated leukemia that inform novel therapeutic approaches. This article is highlighted in the In This Issue feature, p. 85., (©2021 American Association for Cancer Research.)

Somatic mutation in TET2 gene is one of the most common clonal genetic events detected in age-related clonal hematopoiesis as well as in chronic myelomonocytic leukemia (CMML). In addition to being a pre-malignant state, TET2 mutated clones are associated with an increased risk of death from cardiovascular disease, which could involve cytokine/chemokine overproduction by monocytic cells. Here, we show in mice and in human cells that, in the absence of any inflammatory challenge, TET2 downregulation promotes the production of MIF (macrophage migration inhibitory factor), a pivotal mediator of atherosclerotic lesion formation. In healthy monocytes, TET2 is recruited to MIF promoter and interacts with the transcription factor EGR1 and histone deacetylases. Disruption of these interactions as a consequence of TET2-decreased expression favors EGR1-driven transcription of MIF gene and its secretion. MIF favors monocytic differentiation of myeloid progenitors. These results designate MIF as a chronically overproduced chemokine and a potential therapeutic target in patients with clonal TET2 downregulation in myeloid cells., (© 2022. The Author(s).)

An enhanced requirement for nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a dependency in this disease. We demonstrate that SLC5A3 is essential to support a myo-inositol auxotrophy in AML. The commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1 , which encodes the rate-limiting enzyme for myo-inositol biosynthesis, inositol-3-phosphate synthase 1. We use gain- and loss-of-function experiments to reveal a synthetic lethal genetic interaction between ISYNA1 and SLC5A3 in AML, which function redundantly to sustain intracellular myo-inositol. Transcriptional silencing and DNA hypermethylation of ISYNA1 occur in a recurrent manner in human AML patient samples, in association with IDH1/IDH2 and CEBPA mutations. Our findings reveal myo-inositol as a nutrient dependency in AML caused by the aberrant silencing of a biosynthetic enzyme. SIGNIFICANCE: We show how epigenetic silencing can provoke a nutrient dependency in AML by exploiting a synthetic lethality relationship between biosynthesis and transport of myo-inositol. Blocking the function of this solute carrier may have therapeutic potential in an epigenetically defined subset of AML. This article is highlighted in the In This Issue feature, p. 275 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Myelodysplastic syndromes (MDS) are hematopoietic stem and progenitor cell (HSPC) malignancies characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Epigenetic regulators are recurrently mutated in MDS, directly implicating epigenetic dysregulation in MDS pathogenesis. Here, we identified a tumor suppressor role of the acetyltransferase p300 in clinically relevant MDS models driven by mutations in the epigenetic regulators TET2, ASXL1, and SRSF2. The loss of p300 enhanced the proliferation and self-renewal capacity of Tet2-deficient HSPCs, resulting in an increased HSPC pool and leukemogenicity in primary and transplantation mouse models. Mechanistically, the loss of p300 in Tet2-deficient HSPCs altered enhancer accessibility and the expression of genes associated with differentiation, proliferation, and leukemia development. Particularly, p300 loss led to an increased expression of Myb, and the depletion of Myb attenuated the proliferation of HSPCs and improved the survival of leukemia-bearing mice. Additionally, we show that chemical inhibition of p300 acetyltransferase activity phenocopied Ep300 deletion in Tet2-deficient HSPCs, whereas activation of p300 activity with a small molecule impaired the self-renewal and leukemogenicity of Tet2-deficient cells. This suggests a potential therapeutic application of p300 activators in the treatment of MDS with TET2 inactivating mutations.

Hundreds of genes become aberrantly silenced in acute myeloid leukemia (AML), with most of these epigenetic changes being of unknown functional consequence. Here, we demonstrate how gene silencing can lead to an acquired dependency on the DNA repair machinery in AML. We make this observation by profiling the essentiality of the ubiquitination machinery in cancer cell lines using domain-focused CRISPR screening, which revealed Fanconi anemia (FA) proteins UBE2T and FANCL as unique dependencies in AML. We demonstrate that these dependencies are due to a synthetic lethal interaction between FA proteins and aldehyde dehydrogenase 2 (ALDH2), which function in parallel pathways to counteract the genotoxicity of endogenous aldehydes. We show DNA hypermethylation and silencing of ALDH2 occur in a recurrent manner in human AML, which is sufficient to confer FA pathway dependency. Our study suggests that targeting of the ubiquitination reaction catalyzed by FA proteins can eliminate ALDH2-deficient AML. SIGNIFICANCE: Aberrant gene silencing is an epigenetic hallmark of human cancer, but the functional consequences of this process are largely unknown. In this study, we show how an epigenetic alteration leads to an actionable dependency on a DNA repair pathway through the disabling of genetic redundancy. This article is highlighted in the In This Issue feature, p. 2113 ., (©2021 American Association for Cancer Research.)

Epigenetic deregulation is now a well-recognized although not yet fully understood mechanism that contributes to the development and progression of myeloid malignancies. In the past 15 years, next-generation sequencing studies have revealed patterns of aberrant DNA methylation, altered chromatin states, and mutations in chromatin modifiers across the spectrum of myeloid malignancies. Studies into the mechanisms that drive these diseases through mouse modeling have helped identify new avenues for therapeutic interventions, from initial treatment to resistant or relapsed disease. This is particularly significant when chemotherapy with cytotoxic agents remains the general standard of care. In this review, we will discuss some of the recent findings of epigenetic mechanisms and how these are informing the development of more targeted strategies for therapeutic intervention in myeloid malignancies., (© 2021 by The American Society of Hematology.)

As the worldwide population continues to rise, so does global demand for agricultural production. This scenario of uncertain food supply is exacerbated by the high salinization of soils worldwide, a serious constraint to crop productivity. In this context, there is an increasing need for alternative sustainable crops. Halophytes are thought to be a promising alternative food source due to their natural ability to grow in saline soils and their multiple potential uses in the food industry. In this study, the protein and fatty acid content of the halophyte Halimione (Atriplex) portulacoides (L.) was studied in different saline conditions. Although more studies are needed to explore the nutritional properties of H. portulacoides, the data presented here suggest that this halophyte should be considered as a promising food crop for saline agriculture., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point to the implication of the mitogen-activated protein kinase (MAPK) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine-like protein 1 (CYTL1) promotes extracellular signal-regulated kinase (ERK) activation through C-C chemokine receptor type 2 (CCR2). Combined MAPK and MCL1 inhibition restores apoptosis of monocytes from patients with CMML and reduces the expansion of patient-derived xenografts in mice. These results show that the combined inhibition of MCL1 and MAPK is a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis., (© 2021 by The American Society of Hematology.)

Azacitidine and enasidenib are two therapies available for treatment of acute myelogenous leukemia (AML), and the mechanisms of action of these drugs involve alteration of aberrant DNA methylation. We hypothesized that a combination of these agents could have interactive effects on DNA methylation and enhance differentiation in mIDH2 cells. Combination treatment enhanced cellular differentiation in TF-1 cells overexpressing IDJ2R140Q through increased hemoglobinization and increased hemoglobin γ RNA expression compared with the effects of single agents. Furthermore, in primary AML samples (IDH2R140Q or R172K), combination treatment reduced CD34+ cells and increased CD15+ cells to a greater extent than attained with single agents. To explore the mechanism of enhanced differentiation with combination treatment, the TF-1 epigenome was analyzed by profiling 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) DNA methylation changes. Enasidenib treatment alone increased 5hmC, consistent with reactivation of ten-eleven-translocation (TET) enzyme activity. Compared with treatment with azacitidine alone, combination treatment reduced 5mC levels at greater numbers of sites and these loci were significantly enriched in regions with increased 5hMC (25.8% vs. 7.4%). Results are consistent with a model in which enasidenib-mediated reactivation of ten-eleven-translocation enzymes cooperates with azacitidine-mediated inhibition of DNA methyltransferase enzymes, leading to greater reductions in DNA methylation and enhanced erythroid differentiation., Competing Interests: Conflict of interest disclosure KJM, VSC, LT, BZ, BA, WLS, MS, and JFD are employees of and/or hold stock in Bristol Myers Squibb (formerly Celgene Corp.). MEF declares no conflicts of interest. LQ has received research funding from Celgene., (Copyright © 2021 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Our understanding of the effects of aging on human hematopoiesis has advanced significantly in recent years, yet the full ramifications of these findings are not fully understood. This review summarizes these findings and discusses their implication as they relate to malignant hematopoiesis., Recent Findings: With human aging there is an impaired immune response, loss of hematopoietic stem cell (HSC) function, increase in clonal hematopoiesis, and higher frequency of myeloid malignancies. Although murine models have implicated abnormalities in DNA damage repair, autophagy, metabolism, and epigenetics, studies in primary human specimens are more limited. The development of age-related clonal hematopoiesis and the risk associated with this is one of the major findings in the field of recent years. This is accompanied by changes in bone marrow stem and progenitor composition, changes in the epigenetic program of stem cells and an inflammatory milieu in the bone marrow. The precise consequences of these changes for the development of age-related malignancies are still unclear., Summary: Advances in the field have begun to reveal the mechanisms driving human HSC loss of function with age. It will be critical to delineate between normal and malignant aging in order to better prevent age-associated myeloid malignancies.

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide, with human papillomavirus (HPV)-related HNSCC rising to concerning levels. Extensive clinical, genetic and epigenetic differences exist between HPV-associated HNSCC and HPV-negative HNSCC, which is often linked to tobacco use. However, 5-hydroxymethylation (5hmC), an oxidative derivative of DNA methylation and its heterogeneity among HNSCC subtypes, has not been studied., Results: We characterized genome-wide 5hmC profiles in HNSCC by HPV status and subtype in 18 HPV(+) and 18 HPV(-) well-characterized tumors. Results showed significant genome-wide hyper-5hmC in HPV(-) tumors, with both promoter and enhancer 5hmC able to distinguish meaningful tumor subgroups. We identified specific genes whose differential expression by HPV status is driven by differential hydroxymethylation. CDKN2A (p16), used as a key biomarker for HPV status, exhibited the most extensive hyper-5hmC in HPV(+) tumors, while HPV(-) tumors showed hyper-5hmC in CDH13, TIMP2, MMP2 and other cancer-related genes. Among the previously reported two HPV(+) subtypes, IMU (stronger immune response) and KRT (more keratinization), the IMU subtype revealed hyper-5hmC and up-regulation of genes in cell migration, and hypo-5hmC with down-regulation in keratinization and cell junctions. We experimentally validated our key prediction of higher secreted and intracellular protein levels of the invasion gene MMP2 in HPV(-) oral cavity cell lines., Conclusion: Our results implicate 5hmC in driving differences in keratinization, cell junctions and other cancer-related processes among tumor subtypes. We conclude that 5hmC levels are critical for defining tumor characteristics and potentially used to define clinically meaningful cancer patient subgroups.

Hematopoietic stem and progenitor cells (HSPC) experience a functional decline in response to chronic inflammation or aging. Haploinsufficiency of A20, or TNFAIP3, an innate immune regulator, is associated with a variety of autoimmune, inflammatory, and hematologic malignancies. Based on a prior analysis of epigenomic and transcriptomic changes during normal human aging, we find that the expression of A20 is significantly reduced in aged HSPC as compared to young HSPC. Here, we show that the partial reduction of A20 expression in young HSPC results in characteristic features of aging. Specifically, heterozygous deletion of A20 in hematopoietic cells resulted in expansion of the HSPC pool, reduced HSPC fitness, and myeloid-biased hematopoiesis. These findings suggest that altered expression of A20 in HSPC contributes to an aging-like phenotype, and that there may be a common underlying mechanism for diminished HSPC function between inflammatory states and aging., (Copyright © 2020 Smith, Culver-Cochran, Adelman, Rhyasen, Ma, Figueroa and Starczynowski.)

Background: The three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. As a key regulator of genome organization, CCCTC-binding factor (CTCF) has been characterized as a DNA-binding protein with important functions in maintaining the topological structure of chromatin and inducing DNA looping. Among the prolific binding sites in the genome, several events with altered CTCF occupancy have been reported as associated with effects in physiology or disease. However, hitherto there is no comprehensive survey of genome-wide CTCF binding patterns across different human cancers., Results: To dissect functions of CTCF binding, we systematically analyze over 700 CTCF ChIP-seq profiles across human tissues and cancers and identify cancer-specific CTCF binding patterns in six cancer types. We show that cancer-specific lost and gained CTCF binding events are associated with altered chromatin interactions, partially with DNA methylation changes, and rarely with sequence mutations. While lost bindings primarily occur near gene promoters, most gained CTCF binding events exhibit enhancer activities and are induced by oncogenic transcription factors. We validate these findings in T cell acute lymphoblastic leukemia cell lines and patient samples and show that oncogenic NOTCH1 induces specific CTCF binding and they cooperatively activate expression of target genes, indicating transcriptional condensation phenomena., Conclusions: Specific CTCF binding events occur in human cancers. Cancer-specific CTCF binding can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer.

Healthy bone marrow progenitors yield a co-ordinated balance of hematopoietic lineages. This balance shifts with aging toward enhanced granulopoiesis with diminished erythropoiesis and lymphopoiesis, changes which likely contribute to the development of bone marrow disorders in the elderly. In this study, RUNX3 was identified as a hematopoietic stem and progenitor cell factor whose levels decline with aging in humans and mice. This decline is exaggerated in hematopoietic stem and progenitor cells from subjects diagnosed with unexplained anemia of the elderly. Hematopoietic stem cells from elderly unexplained anemia patients had diminished erythroid but unaffected granulocytic colony forming potential. Knockdown studies revealed human hematopoietic stem and progenitor cells to be strongly influenced by RUNX3 levels, with modest deficiencies abrogating erythroid differentiation at multiple steps while retaining capacity for granulopoiesis. Transcriptome profiling indicated control by RUNX3 of key erythroid transcription factors, including KLF1 and GATA1 These findings thus implicate RUNX3 as a participant in hematopoietic stem and progenitor cell aging, and a key determinant of erythroid-myeloid lineage balance., (Copyright© 2020 Ferrata Storti Foundation.)

Background: Conceptualizing gender dynamics and ways of bridging entrenched gender roles will contribute to better health promotion, policy and planning. Such processes are explored in relation to malaria in Mozambique., Methods: A multi-method, qualitative study using focus group discussions (FGDs) and in-depth interviews (IDIs) explored the perspectives of community members, leaders and stakeholders on malaria. The study was conducted in Nampula Province, in an intervention district for the Tchova Tchova Stop Malaria (TTSM) gender-sensitive community dialogues, and in a non-intervention district., Results: Participants (n = 106) took part in six FGDs and five IDIs in each district. Those exposed to TTSM commonly stated that the programme influenced more equalitarian gender roles, attitudes and uptake of protective malaria-related practices. These positive changes occurred within the context of an observed, gendered decision-making matrix, which aligns inward- or outward-facing decisions with malaria prevention or treatment. Decisions more dependent on male or elder sanctioning at community level are outward-facing decisions, while decisions falling within women's domain at household level are inward-facing decisions. Related to prevention, using bed nets was largely an inward-facing prevention decision for women, who were generally tasked with hanging, washing and making nets usable. Net purchase and appropriation for malaria prevention (rather than for instance for fishing) was men's prerogative. Regular net use was associated with sleeping together more regularly, bringing couples closer. Attending antenatal care to access intermittent preventive treatment during pregnancy was often an outward-facing prevention decision, under the purview of older, influential women and ultimately needing sanctioning by men. With respect to seeking care for malaria symptoms, women typically sought help from traditional healers first. This inward-facing treatment decision was within their control, in contrast to the frequently transport-dependent, outward-facing decision to attend a health facility. Sharing decisions was described as a feature of a "harmonious household," something that was said to be encouraged by the TTSM intervention and that was both lived and aspirational., Conclusions: TTSM community dialogues helped communication on both interpersonal (couple) and community levels, ultimately encouraging malaria-related behaviours. Leveraging ways of bringing men and women together to share decision making will improve malaria intervention success.

Transforming growth factor beta (TGFβ) signalling is involved in several aspects of regeneration in many organs and tissues of primitive vertebrates. It has been difficult to recognize the role of this signal in mammal regeneration due to the low ability of this animal class to reconstitute tissues. Nevertheless, ear-holes in middle-age female mice represent a model to study the limited epimorphic-like regeneration in mammals. Using this model, in this study we explored the possible participation of TGFβ signalling in mammal regeneration. Positive pSmad3 cells, as well as TGFβ1 and TGFβ3 isoforms, were detected during the redifferentiation phase in the blastema-like structure. Daily administration of the inhibitor of the TGFβ intracellular pathway, SB431542, during 7 days from the re-differentiation phase, resulted in a decreased level of pSmad3 accompanied by a transitory higher growth of the new tissue, larger cartilage nodules, and new muscle formation. These phenotypes were associated with a decrease in the number of α-SMA-positive cells and loose packing of collagen I. These results indicate that the modulation of the fibrosis mediated by TGFβ signalling contributes to enhancing the differentiation of cartilage and muscle during limited ear-hole regeneration.

The functional diversity of cells that compose myeloid malignancies, i.e., the respective roles of genetic and epigenetic heterogeneity in this diversity, remains poorly understood. This question is addressed in chronic myelomonocytic leukemia, a myeloid neoplasm in which clinical diversity contrasts with limited genetic heterogeneity. To generate induced pluripotent stem cell clones, we reprogrammed CD34 + cells collected from a patient with a chronic myelomonocytic leukemia in which whole exome sequencing of peripheral blood monocyte DNA had identified 12 gene mutations, including a mutation in KDM6A and two heterozygous mutations in TET2 in the founding clone and a secondary KRAS (G12D) mutation. CD34 + cells from an age-matched healthy donor were also reprogrammed. We captured a part of the genetic heterogeneity observed in the patient, i.e. we analyzed five clones with two genetic backgrounds, without and with the KRAS (G12D) mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient's disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior of hematopoietic cells derived from induced pluripotent stem cell clones with similar genetic background, correlating with limited epigenetic changes. These analyses suggest that, beyond the coding mutations, several levels of intraclonal heterogeneity may participate in the yet unexplained clinical heterogeneity of the disease., (Copyright© 2020 Ferrata Storti Foundation.)

The unbalanced translocation dic(1;7)(q10;p10) in myelodysplastic syndromes (MDS) is originated by centromeric juxtaposition resulting into 1q trisomy and 7q monosomy. More than half of cases arise after chemo/radio-therapy. To date, given the absence of genes within the centromeric regions, no specific molecular events have been identified in this cytogenetic subgroup. We performed the first comprehensive genetic and epigenetic analysis of MDS with dic(1;7)(q10;p10) compared to normal controls and therapy-related myeloid neoplasms (t-MNs). RNA-seq showed a unique downregulated signature in dic(1;7) cases, affecting more than 80% of differentially expressed genes. As revealed by pathway and gene ontology analyses, downregulation of ATP-binding cassette (ABC) transporters and lipid-related genes and upregulation of p53 signaling were the most relevant biological features of dic(1;7). Epigenetic supervised analysis revealed hypermethylation at intronic enhancers in the dicentric subgroup, in which low expression levels of enhancer putative target genes accounted for around 35% of the downregulated signature. Enrichment of Krüppel-like transcription factor binding sites emerged at enhancers. Furthermore, a specific hypermethylated pattern on 1q was found to underlie the hypo-expression of more than 50% of 1q-deregulated genes, despite trisomy. In summary, dic(1;7) in MDS establishes a specific transcriptional program driven by a unique epigenomic signature.

Aging is associated with functional decline of hematopoietic stem cells (HSC) as well as an increased risk of myeloid malignancies. We performed an integrative characterization of epigenomic and transcriptomic changes, including single-cell RNA sequencing, during normal human aging. Lineage - CD34 + CD38 - cells [HSC-enriched (HSCe)] undergo age-associated epigenetic reprogramming consisting of redistribution of DNA methylation and reductions in H3K27ac, H3K4me1, and H3K4me3. This reprogramming of aged HSCe globally targets developmental and cancer pathways that are comparably altered in acute myeloid leukemia (AML) of all ages, encompassing loss of 4,646 active enhancers, 3,091 bivalent promoters, and deregulation of several epigenetic modifiers and key hematopoietic transcription factors, such as KLF6, BCL6, and RUNX3. Notably, in vitro downregulation of KLF6 results in impaired differentiation, increased colony-forming potential, and changes in expression that recapitulate aging and leukemia signatures. Thus, age-associated epigenetic reprogramming may form a predisposing condition for the development of age-related AML. SIGNIFICANCE: AML, which is more frequent in the elderly, is characterized by epigenetic deregulation. We demonstrate that epigenetic reprogramming of human HSCs occurs with age, affecting cancer and developmental pathways. Downregulation of genes epigenetically altered with age leads to impairment in differentiation and partially recapitulates aging phenotypes. This article is highlighted in the In This Issue feature, p. 983 ., (©2019 American Association for Cancer Research.)

Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1 R132H ) are younger at diagnosis and live longer. IDH1 mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53 (TP53 ) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene ( ATRX ). All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1 R132H mutation. The current molecular classification of LGGs is based, partly, on the distribution of these mutations. We developed a genetically engineered mouse model harboring IDH1 R132H , TP53 and ATRX inactivating mutations, and activated NRAS G12V. Previously, we established that ATRX deficiency, in the context of wild-type IDH1, induces genomic instability, impairs nonhomologous end-joining DNA repair, and increases sensitivity to DNA-damaging therapies. In this study, using our mouse model and primary patient-derived glioma cultures with IDH1 mutations, we investigated the function of IDH1 R132H in the context of TP53 and ATRX loss. We discovered that IDH1 R132H expression in the genetic context of ATRX and TP53 gene inactivation (i) increases median survival in the absence of treatment, (ii) enhances DNA damage response (DDR) via epigenetic up-regulation of the ataxia-telangiectasia-mutated (ATM) signaling pathway, and (iii) elicits tumor radioresistance. Accordingly, pharmacological inhibition of ATM or checkpoint kinases 1 and 2, essential kinases in the DDR, restored the tumors' radiosensitivity. Translation of these findings to patients with IDH1 132H glioma harboring TP53 and ATRX loss could improve the therapeutic efficacy of radiotherapy and, consequently, patient survival., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

TET2 somatic mutations occur in ∼10% of diffuse large B-cell lymphomas (DLBCL) but are of unknown significance. Herein, we show that TET2 is required for the humoral immune response and is a DLBCL tumor suppressor. TET2 loss of function disrupts transit of B cells through germinal centers (GC), causing GC hyperplasia, impaired class switch recombination, blockade of plasma cell differentiation, and a preneoplastic phenotype. TET2 loss was linked to focal loss of enhancer hydroxymethylation and transcriptional repression of genes that mediate GC exit, such as PRDM1. Notably, these enhancers and genes are also repressed in CREBBP -mutant DLBCLs. Accordingly, TET2 mutation in patients yields a CREBBP -mutant gene-expression signature, CREBBP and TET2 mutations are generally mutually exclusive, and hydroxymethylation loss caused by TET2 deficiency impairs enhancer H3K27 acetylation. Hence, TET2 plays a critical role in the GC reaction, and its loss of function results in lymphomagenesis through failure to activate genes linked to GC exit signals. SIGNIFICANCE: We show that TET2 is required for exit of the GC, B-cell differentiation, and is a tumor suppressor for mature B cells. Loss of TET2 phenocopies CREBBP somatic mutation. These results advocate for sequencing TET2 in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors. See related commentary by Shingleton and Dave, p. 1515 . This article is highlighted in the In This Issue feature, p. 1494 ., (©2018 American Association for Cancer Research.)

Interspecific hybridization is an important and common evolutionary mechanism, but field-based evaluations of changes in realized niches and zonation patterns of native and exotic hybrids relative to those of their parental plant species are rare. Would native hybrids forming hybrid zones between their parental species show realized niches similar to that of their parents, whereas would exotic hybrids show larger realized niches than their parents, and alter zonation patterns of native species? To address these questions, we examined key sediment characteristics in plots representing realized niches of native Sarcocornia hybrids, invasive Spartina hybrids and parental species in 14 salt marshes from four estuaries in the Gulf of Cadiz, Southwest Iberian Peninsula. In one representative marsh, the presence of plant taxa relative to intertidal plant zonation was recorded. Results documented that native and fertile hybrids of Sarcocornia had similar realized niche dimensions as their parental species and co-occurred with other plant species, supporting community diversity. However, exotic sterile hybrids of Spartina had realized niche dimensions lower than those of their parental species and occurred in monocultures. The native hybrids played a community structuring role, whereas the exotic Spartina hybrids were a disruptive influence that changed native halophyte zonation pattern and decreased diversity. This negative functional role could intensify if the sterile hybrids evolve and become fertile. Our study suggests the ecological niche dimension concept is an important tool for understanding species roles in ecosystems, incorporating many ideas from the individual to ecosystem levels.

Polycomb repressive complex 1 (PRC1) plays essential roles in cell fate decisions and development. However, its role in cancer is less well understood. Here, we show that RNF2, encoding RING1B, and canonical PRC1 (cPRC1) genes are overexpressed in breast cancer. We find that cPRC1 complexes functionally associate with ERα and its pioneer factor FOXA1 in ER+ breast cancer cells, and with BRD4 in triple-negative breast cancer cells (TNBC). While cPRC1 still exerts its repressive function, it is also recruited to oncogenic active enhancers. RING1B regulates enhancer activity and gene transcription not only by promoting the expression of oncogenes but also by regulating chromatin accessibility. Functionally, RING1B plays a divergent role in ER+ and TNBC metastasis. Finally, we show that concomitant recruitment of RING1B to active enhancers occurs across multiple cancers, highlighting an under-explored function of cPRC1 in regulating oncogenic transcriptional programs in cancer.

Concurrent genetic lesions exist in a majority of patients with hematologic malignancies. Among these, somatic mutations that activate RAS oncogenes and inactivate the epigenetic modifier ten-eleven translocation 2 ( TET2 ) frequently co-occur in human chronic myelomonocytic leukemias (CMMLs) and acute myeloid leukemias, suggesting a cooperativity in malignant transformation. To test this, we applied a conditional murine model that endogenously expressed oncogenic Nras G12D and monoallelic loss of Tet2 and explored the collaborative role specifically within hematopoietic stem and progenitor cells (HSPCs) at disease initiation. We demonstrate that the 2 mutations collaborated to accelerate a transplantable CMML-like disease in vivo, with an overall shortened survival and increased disease penetrance compared with single mutants. At preleukemic stage, N-Ras G12D and Tet2 haploinsufficiency together induced balanced hematopoietic stem cell (HSC) proliferation and enhanced competitiveness. Nras G12D/+ / Tet2 +/- HSCs displayed increased self-renewal in primary and secondary transplantations, with significantly higher reconstitution than single mutants. Strikingly, the 2 mutations together conferred long-term reconstitution and self-renewal potential to multipotent progenitors, a pool of cells that usually have limited self-renewal compared with HSCs. Moreover, HSPCs from Nras G12D/+ / Tet2 +/- mice displayed increased cytokine sensitivity in response to thrombopoietin. Therefore, our studies establish a novel tractable CMML model and provide insights into how dysregulated signaling pathways and epigenetic modifiers collaborate to modulate HSPC function and promote leukemogenesis., (© 2018 by The American Society of Hematology.)

IL-1 and TNF-α are always present during wound repair, but their pleiotropic and synergistic effects are incompletely understood. In this work, we evaluated the role of IL-1 in wound repair, and examined whether TNF-α administration impaired scarless wound repair. First, we characterised wound repair in outbred CD-1 mice according to age and sex in an ear punch wound model. Then, we examined the effects of Interleukin 1 receptor antagonist (IL-1ra) and TNF-α placement inside ear wounds by means of loaded Heparin beads in young and middle-aged male and female mice. Wounds in middle-aged females repaired with scarless characteristics, whereas those in young males showed fibrotic scarring. Rather than improving wound repair in young males, IL-1 signalling blockade increased epithelial thickness and IL-1β and TNF-α expression, and diminished epidermal apoptosis. TNF-α impaired wound repair in middle-aged females, which exhibited acanthosis and overexpression of IL-1, but no change in apoptosis. These findings suggest that this mechanism of epidermal thickening differs from that observed in IL1-ra-treated animals., (Copyright © 2017 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)

We compared the impact of a commercial chlorination product (brand name Air RahMat) in stored drinking water to traditional boiling practices in Indonesia. We conducted a baseline survey of all households with children 1000 MPN/100 ml (RR 1·86, 95% CI 1·09-3·19) in stored water than in households without detectable E. coli. Although results suggested that Air RahMat water treatment was associated with lower E. coli contamination and diarrhoeal rates among children <5 years than water treatment by boiling, Air RahMat use remained low.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors, and comprises ~15% and 25% of pediatric and adult ALL cases, respectively. It is well-established that activating NOTCH1 mutations are the major genetic lesions driving T-ALL in most patients, but efforts to develop targeted therapies against this pathway have produced limited success in decreasing leukemic burden and come with significant clinical side effects. A finer detailed understanding of the genetic and molecular mechanisms underlying T-ALL is required identify patients at increased risk for treatment failure and the development of precision medicine strategies. Generation of genetic models that more accurately reflect the normal developmental history of T-ALL are necessary to identify new avenues for treatment. The DNA methyltransferase enzyme DNMT3A is also recurrently mutated in T-ALL patients, and we show here that inactivation of Dnmt3a combined with Notch1 gain-of-function leads to an aggressive T-ALL in mouse models. Moreover, conditional inactivation of Dnmt3a in mouse hematopoietic cells leads to an accumulation of immature progenitors in the thymus, which are less apoptotic. These data demonstrate that Dnmt3a is required for normal T-cell development, and acts as a T-ALL tumor suppressor.