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Activation of the tyrosine kinase c-Src promotes breast cancer progression and poor outcomes, yet the underlying mechanisms are incompletely understood. Here, we have shown that deletion of c-Src in a genetically engineered model mimicking the luminal B molecular subtype of breast cancer abrogated the activity of forkhead box M1 (FOXM1), a master transcriptional regulator of the cell cycle. We determined that c-Src phosphorylated FOXM1 on 2 tyrosine residues to stimulate its nuclear localization and target gene expression. These included key regulators of [G.sub.2]/M cell-cycle progression as well as c-Src itself, forming a positive feedback loop that drove proliferation in genetically engineered and patient-derived models of luminal B-like breast cancer. Using genetic approaches and small molecules that destabilize the FOXM1 protein, we found that targeting this mechanism induced [G.sub.2]/M cell-cycle arrest and apoptosis, blocked tumor progression, and impaired metastasis. We identified a positive correlation between FOXM1 and c-Src expression in human breast cancer and show that the expression of FOXM1 target genes predicts poor outcomes and associates with the luminal B subtype, which responds poorly to currently approved therapies. These findings revealed a regulatory network centered on c-Src and FOXM1 that is a targetable vulnerability in aggressive luminal breast cancers., Introduction Breast cancer comprises a range of histopathological and molecular subtypes differing in metastatic capacity, response to therapies, and clinical outcomes (1). Transcriptomic profiling has identified at least 5 breast [...]

This paper proposes some interdisciplinary design education approaches which can help to introduce students to more holistic perspectives of design practice, the world, and the influence of design within it. Through reflection on our design education practice, the authors highlight particular benefits of integrative design pedagogy to increase student awareness of relationships between disciplines, systems thinking, ability to design for ‘synergy’, and to more adequately prepare designers for an increasingly interconnected and changing world. Case study as a qualitative methodology is utilised to reflect on our interdisciplinary design studio educational practice (Baskarada, 2014; Rashid et al., 2019). Reflective practice methodology is also used to critically reflect on the design education case studies (Brookfield, 2000; Osterman, 1990). Key findings from these case studies suggest that teaching both 2D and 3D design fundamentals in combination, and having real world projects, can give students more awareness of the interrelatedness of design disciplines and foster systems thinking from early in their design studies/careers. Non-assessed collaboration between students from different programmes also needs to be encouraged and facilitated. Introducing critical reflective approaches are also important, to give learners deeper understandings of the implications of design and the importance of designing to counteract ‘wicked problems’.

The article discusses the validation of the BAUSSS biomarker as a risk staging tool for patients with primary melanoma. The BAUSSS algorithm incorporates Breslow thickness, age, ulceration, subtype, sex, and site to assess prognosis. The authors compare the BAUSSS biomarker to other nomograms and conclude that Lifemath is the most reliable online tool for melanoma prognosis. They address concerns raised by another study and maintain that BAUSSS is a simple and effective predictor of survival risk in melanoma patients. The addition of sentinel lymph node biopsy status to BAUSSS improves accuracy but may not be meaningful in all cases. [Extracted from the article]

Introduction: Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability of endogenous annulus fibrosus (AF) cells to respond to injury and drive tissue regeneration. Unlike other orthopedic tissues, such as cartilage, delivery of exogenous cells to the site of annular injury remains underdeveloped, largely due to a lack of an ideal cell source and the invasive nature of cell isolation. Human induced pluripotent stem cells (iPSCs) can be differentiated to specific cell fates using biochemical factors and are, therefore, an invaluable tool for cell therapy approaches. While differentiation protocols have been developed for cartilage and fibrous connective tissues (e.g., tendon), the signals that regulate the induction and differentiation of human iPSCs toward the AF fate remain unknown. Methods: iPSC‐derived sclerotome cells were treated with various combinations of developmental signals including transforming growth factor beta 3 (TGF‐β3), connective tissue growth factor (CTGF), platelet derived growth factor BB (PDGF‐BB), insulin‐like growth factor 1 (IGF‐1), or the Hedgehog pathway activator, Purmorphamine, and gene expression changes in major AF‐associated ECM genes were assessed. The top performing combination treatments were further validated by using three distinct iPSC lines and by assessing the production of upregulated ECM proteins of interest. To conduct a broader analysis of the transcriptomic shifts elicited by each factor combination, and to compare genetic profiles of treated cells to mature human AF cells, a 96.96 Fluidigm gene expression array was applied, and principal component analysis was employed to identify the transcriptional signatures of each cell population and treatment group in comparison to native AF cells. Results: TGF‐β3, in combination with PDGF‐BB, CTGF, or IGF‐1, induced an upregulation of key AF ECM genes in iPSC‐derived sclerotome cells. In particular, treatment with a combination of TGF‐β3 with PDGF‐BB for 14 days significantly increased gene expression of collagen II and aggrecan and increased protein deposition of collagen I and elastin compared to other treatment groups. Assessment of genes uniquely highly expressed by AF cells or SCL cells, respectively, revealed a shift toward the genetic profile of AF cells with the addition of TGF‐β3 and PDGF‐BB for 14 days. Discussion: These findings represent an initial approach to guide human induced pluripotent stem cells toward an AF‐like fate for cellular delivery strategies. [ABSTRACT FROM AUTHOR]