Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling.

Acute myeloid leukaemia (AML) is a haematological malignancy characterised by the accumulation of transformed myeloid progenitors in the bone marrow. Piplartine (PL), also known as piperlongumine, is a pro-oxidant small molecule extracted from peppers that has demonstrated antineoplastic potential in solid tumours and other haematological malignancies. In this work, we explored the potential of PL to treat AML through the use of a combination of cellular and molecular analyses of primary and cultured leukaemia cells in vitro and in vivo. We showed that PL exhibits in vitro cytotoxicity against AML cells, including CD34+ leukaemia-propagating cells, but not healthy haematopoietic progenitors, suggesting anti-leukaemia selectivity. Mechanistically, PL treatment increased reactive oxygen species (ROS) levels and induced ROS-mediated apoptosis in AML cells, which could be prevented by treatment with the antioxidant scavenger N-acetyl-cysteine and the pancaspase inhibitor Z-VAD(OMe)-FMK. PL treatment reduced NFKB1 gene transcription and the level of NF-κB p65 (pS536), which was depleted from the nucleus of AML cells, indicating suppression of NF-κB p65 signalling. Significantly, PL suppressed AML development in a mouse xenograft model, and its combination with current AML treatments (cytarabine, daunorubicin and azacytidine) had synergistic effects, indicating translational therapeutic potential. Taken together, these data position PL as a novel anti-AML candidate drug that can target leukaemia stem/progenitors and is amenable to combinatorial therapeutic strategies.

Integrating Palliative Care Into the ICU: From Core Competency to Consultative Expertise.

OBJECTIVES: To propose a model describing levels of integration of palliative care into the care of ICU patients. DATA SOURCES: Literature review and author opinion. CONCLUSIONS: All critical care team members should demonstrate and foster their core competencies in caring for patients with complex illness and uncertain prognosis, including at the end of life. We describe these core competencies of the ICU team member as "primary" palliative care skills. Some ICU team members will have special expertise in end-of-life care or symptom management and decision-making support and will serve as local experts within the ICU team as a resource to other team members. We call this skillset "secondary" palliative care. Some patients will benefit from the full range of expertise provided by a separate consulting team, with additional training, focused on caring for patients with palliative care needs across the full spectrum of patient locations within a health system. We term the skillset provided by such outside consultants "tertiary" palliative care. Solutions for meeting patients' palliative care needs will be unique within each system and individual institution, depending on available resources, history, and structures in place. Providers from multiple professions will usually contribute to meeting patient needs.