Combination of curaxin and tyrosine kinase inhibitors display enhanced killing of primitive Chronic Myeloid Leukaemia cells

Despite the big increase in precision medicine targeted therapies developing curative treatments for many cancers is still a major challenge due mainly to the development of drug resistance in cancer stem cells. The cancer stem cells are constantly evolving to survive and targeted drug treatment often increases the selective pressure on these cells from which the disease develops. Chronic myeloid leukaemia is a paradigm of cancer stem cell research. Targeted therapies to the causative oncogene, BCR/ABL, have been developed but drug resistance remains a problem. The introduction of tyrosine kinase inhibitors targeting BCR/ABL were transformative in the management of CML. However, patients are rarely cured as the tyrosine kinase inhibitors fail to eradicate the leukaemic stem cell which often leads to loss of response to therapy as drug resistance develops and progression to more fatal forms of acute leukaemia occurs. New treatment strategies targeting other entities within the leukemic stem cell either alone or in combination with tyrosine kinase are therefore required. Drawing on our previous published work on the development of potential novel targets in CML and other myeloproliferative diseases along with analysis of the facilitates chromatin transcription (FACT) complex in CML we hypothesised that curaxin, a drug that targets the FACT complex and is in clinical trial for the treatment of other cancers, could be of use in the treatment of CML. We therefore assessed the curaxin CBL0137 as a new agent to extinguish CML primitive cells and show its ability to preferentially target CML cells compared to healthy control cells, especially in combination with clinically relevant tyrosine kinase inhibitors

Ariel - Volume 10 Number 5

Executive Editors Madalyn Schaefgen David Reich Business Manager David Reich News Editors Medical College Edward Zurad CAHS John Guardiani World Mark Zwanger Features Editors Meg Trexler Jim O\u27Brien Editorials Editor Jeffrey Banyas Photography and Sports Editor Stuart Singer Commons Editor Brenda Peterso

IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type 2 immune response to nematode infection

Peer reviewedPublisher PD

Can digital stories go where palliative care research has never gone before? A descriptive qualitative study exploring the application of an emerging public health research method in an indigenous palliative care context.

BACKGROUND: The World Health Organization (WHO) has called for global approaches to palliative care development. Yet it is questionable whether one-size-fits-all solutions can accommodate international disparities in palliative care need. More flexible research methods are called for in order to understand diverse priorities at local levels. This is especially imperative for Indigenous populations and other groups underrepresented in the palliative care evidence-base. Digital storytelling (DST) offers the potential to be one such method. Digital stories are short first-person videos that tell a story of great significance to the creator. The method has already found a place within public health research and has been described as a useful, emergent method for community-based participatory research. METHODS: The aim of this study was to explore Māori participants' views on DST's usefulness, from an Indigenous perspective, as a research method within the discipline of palliative care. The digital storytelling method was adapted to include Māori cultural protocols. Data capturing participant experience of the study were collected using participant observation and anonymous questionnaires. Eight participants, seven women and one man, took part. Field notes and questionnaire data were analysed using critical thematic analysis. RESULTS: Two main themes were identified during analyses: 1) issues that facilitated digital storytelling's usefulness as a research method for Māori reporting on end of life caregiving; and 2) issues that hindered this process. All subthemes identified: recruitment, the pōwhiri process, (Māori formal welcome of visitors) and technology, related to both main themes and are presented in this way. CONCLUSION: Digital storytelling is an emerging method useful for exploring Indigenous palliative care issues. In line with a Health Promoting Palliative Care approach that centres research in communities, it helps meet the need for diverse approaches to involve underrepresented groups

Integrated analyses of chromatin accessibility and gene expression data for elucidating the transcriptional regulatory mechanisms during early hematopoietic development in mouse

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Embryonic stem cell-derived hemangioblasts remain epigenetically plastic and require PRC1 to prevent neural gene expression.

Many lineage-specific developmental regulator genes are transcriptionally primed in embryonic stem (ES) cells; RNA Pol(II) is bound at their promoters but is prevented from productive elongation by the activity of polycomb repressive complexes (PRC) 1 and 2. This epigenetically poised state is thought to enable ES cells to rapidly execute multiple differentiation programs and is recognized by a simultaneous enrichment for trimethylation of lysine 4 and trimethylation of lysine 27 of histone H3 (bivalent chromatin) across promoter regions. Here we show that the chromatin profile of this important cohort of genes is progressively modified as ES cells differentiate toward blood-forming precursors. Surprisingly however, neural specifying genes, such as Nkx2-2, Nkx2-9, and Sox1, remain bivalent and primed even in committed hemangioblasts, as conditional deletion of PRC1 results in overt and inappropriate expression of neural genes in hemangioblasts. These data reinforce the importance of PRC1 for normal hematopoietic differentiation and reveal an unexpected epigenetic plasticity of mesoderm-committed hemangioblasts

Gender-based violence and its association with mental health among Somali women in a Kenyan refugee camp: a latent class analysis

background In conflict-affected settings, women and girls are vulnerable to gender-based violence (GBV). GBV is associated with poor long-term mental health such as anxiety, depression and post-traumatic stress disorder (PTSD). Understanding the interaction between current violence and past conflict-related violence with ongoing mental health is essential for improving mental health service provision in refugee camps. Methods Using data collected from 209 women attending GBV case management centres in the Dadaab refugee camps, Kenya, we grouped women by recent experience of GBV using latent class analysis and modelled the relationship between the groups and symptomatic scores for anxiety, depression and PTSD using linear regression. Results Women with past-year experience of intimate partner violence alone may have a higher risk of depression than women with past-year experience of non-partner violence alone (Coef. 1.68, 95% CI 0.25 to 3.11). Conflict-related violence was an important risk factor for poor mental health among women who accessed GBV services, despite time since occurrence (average time in camp was 11.5 years) and even for those with a past-year experience of GBV (Anxiety: 3.48, 1.85–5.10; Depression: 2.26, 0.51–4.02; PTSD: 6.83, 4.21–9.44). Conclusion Refugee women who experienced past-year intimate partner violence or conflict-related violence may be at increased risk of depression, anxiety or PTSD. Service providers should be aware that compared to the general refugee population, women who have experienced violence may require additional psychological support and recognise the enduring impact of violence that occurred before, during and after periods of conflict and tailor outreach and treatment services accordingly

Research challenges in evaluating gender-based violence response services in a refugee camp

This article presents a case study of research in Dadaab, Kenya to highlight some of the relevant challenges encountered while conducting gender-based violence research in humanitarian settings. A longitudinal mixed-methods design was used to evaluate a comprehensive case-management intervention in the refugee complex near the border of Kenya and Somalia. We present an overview of both expected and unexpected challenges during preparation and implementation of the research, adaptations made to the research design, and lessons learned for future research in similar contexts. Some of the key challenges were attributed to the highly securitized and remote environment of Dadaab refugee camp, like many refugee camp settings, which created limitations for sampling designs, interview locations, and also created particular burdens for the research team members conducting interviews. In addition to the camp environment, the dynamic nature of events and trends in the camp setting created barriers to follow-up with longitudinal cohort participants as well as uncertainty on how to plan for future implementation of research design phases in response to camp changes. Conducting research in humanitarian settings requires a flexible approach to accommodate the challenges that can impact both service delivery and research activities. The discussion presented in this article contributes to the evolving practical guidance on conducting research in humanitarian settings

Quantitative phosphoproteome analysis of embryonic stem cell differentiation toward blood

Murine embryonic stem (ES) cells can differentiate in vitro into three germ layers (endodermic, mesodermic, ectodermic). Studies on the differentiation of these cells to specific early differentiation stages has been aided by an ES cell line carrying the Green Fluorescent Protein (GFP) targeted to the Brachyury (Bry) locus which marks mesoderm commitment. Furthermore, expression of the Vascular Endothelial Growth Factor receptor 2 (Flk1) along with Bry defines hemangioblast commitment. Isobaric-tag for relative and absolute quantification (iTRAQTM) and phosphopeptide enrichment coupled to liquid chromatography separation and mass spectrometry allow the study of phosphorylation changes occurring at different stages of ES cell development using Bry and Flk1 expression respectively. We identified and relatively quantified 37 phosphoentities which are modulated during mesoderm-induced ES cells differentiation, comparing epiblast-like, early mesoderm and hemangioblast-enriched cells. Among the proteins differentially phosphorylated toward mesoderm differentiation were: the epigenetic regulator Dnmt3b, the protein kinase GSK3b, the chromatin remodeling factor Smarcc1, the transcription factor Utf1; as well as protein specifically related to stem cell differentiation, as Eomes, Hmga2, Ints1 and Rif1. As most key factors regulating early hematopoietic development have also been implicated in various types of leukemia, understanding the post-translational modifications driving their regulation during normal development could result in a better comprehension of their roles during abnormal hematopoiesis in leukemia

The magnitude of airway remodeling is not altered by distinct allergic inflammatory responses in BALB/c versus C57BL/6 mice but matrix composition differs

From Wiley via Jisc Publications RouterHistory: received 2020-10-20, rev-recd 2021-01-23, accepted 2021-02-11, pub-electronic 2021-03-19, pub-print 2021-07Article version: VoRPublication status: PublishedFunder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/K01207X/1, MR/P02615X/1Funder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100010269; Grant(s): 106898/A/15/ZFunder: Asthma UK; Id: http://dx.doi.org/10.13039/501100000362; Grant(s): MRFAUK‐2015‐302Funder: Medical Research Foundation UK; Grant(s): MRFAUK‐2015‐302Abstract: Allergic airway inflammation is heterogeneous with variability in immune phenotypes observed across asthmatic patients. Inflammation has been thought to directly contribute to airway remodeling in asthma, but clinical data suggest that neutralizing type 2 cytokines does not necessarily alter disease pathogenesis. Here, we utilized C57BL/6 and BALB/c mice to investigate the development of allergic airway inflammation and remodeling. Exposure to an allergen cocktail for up to 8 weeks led to type 2 and type 17 inflammation, characterized by airway eosinophilia and neutrophilia and increased expression of chitinase‐like proteins in both C57BL/6 and BALB/c mice. However, BALB/c mice developed much greater inflammatory responses than C57BL/6 mice, effects possibly explained by a failure to induce pathways that regulate and maintain T‐cell activation in C57BL/6 mice, as shown by whole lung RNA transcript analysis. Allergen administration resulted in a similar degree of airway remodeling between mouse strains but with differences in collagen subtype composition. Increased collagen III was observed around the airways of C57BL/6 but not BALB/c mice while allergen‐induced loss of basement membrane collagen IV was only observed in BALB/c mice. This study highlights a model of type 2/type 17 airway inflammation in mice whereby development of airway remodeling can occur in both BALB/c and C57BL/6 mice despite differences in immune response dynamics between strains. Importantly, compositional changes in the extracellular matrix between genetic strains of mice may help us better understand the relationships between lung function, remodeling and airway inflammation