Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt–β-catenin and PI3K–Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt–β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape

WHY HAVE HEPATITIS B BIRTH DOSE RATES DECREASED IN JOHNSON COUNTY? A PRELIMINARY QUALITY IMPROVEMENT PROJECT

Master of Public HealthPublic Health Interdepartmental ProgramThu Annelise NguyenThe World Health Organization recommended that the Hepatitis B vaccination be added to the universal vaccination programs in all countries in 1991. Incidence of acute Hepatitis B in the United States decreased 75% from 1991 – 2004 (Mast et al., 2005). This success not only is due to the WHO, but also due to the United States government supporting Hepatitis B perinatal programs. The United States Advisory Committee on Immunization Practices (ACIP) which recommends all infants are given the Hepatitis B birth dose (Hepatitis B infant vaccine) before being discharged from the hospital. The Vaccines for Children Program from Centers for Disease Control and Prevention (CDC) offers childhood vaccinations at no charge for qualifying individuals. This includes uninsured, underinsured, Medicaid-eligible, Native American, and Native Alaskan children (CDC, Vaccines for Children Program, 2012). Despite efforts made by federal, state, and local governments, between the years 2005 and 2010, Hepatitis B birth dose rates for infants in Johnson County, Kansas have drastically declined – 92.2% coverage in 2005 to 69.9% coverage in 2010. The purpose of this study is to identify problems that act as barriers to receiving the birth dose and to develop Quality Improvement measures to eliminate them. Thoughts were organized and an internal source survey (JCDHE employees) was conducted to put the results into Quality Improvement tools. The outcome of this study will be useful for answering the question of why the Hepatitis B birth dose rate has dropped in Johnson County, Kansas and suggestions to increase the rate of vaccination

Human Peripheral Blood Mononucleocyte Derived Myeloid Committed Progenitor Cells Mitigate H-ARS by Exosomal Paracrine Signal

Radiation-induced loss of the hematopoietic stem cell progenitor population compromises bone marrow regeneration and development of mature blood cells. Failure to rescue bone marrow functions results in fatal consequences from hematopoietic injury, systemic infections, and sepsis. So far, bone marrow transplant is the only effective option, which partially minimizes radiation-induced hematopoietic toxicities. However, a bone marrow transplant will require HLA matching, which will not be feasible in large casualty settings such as a nuclear accident or an act of terrorism. In this study we demonstrated that human peripheral blood mononuclear cell-derived myeloid committed progenitor cells can mitigate radiation-induced bone marrow toxicity and improve survival in mice. These cells can rescue the recipient’s hematopoietic stem cells from radiation toxicity even when administered up to 24 h after radiation exposure and can be subjected to allogenic transplant without GVHD development. Transplanted cells deliver sEVs enriched with regenerative and immune-modulatory paracrine signals to mitigate radiation-induced hematopoietic toxicity. This provides a natural polypharmacy solution against a complex injury process. In summary, myeloid committed progenitor cells can be prepared from blood cells as an off-the-shelf alternative to invasive bone marrow harvesting and can be administered in an allogenic setting to mitigate hematopoietic acute radiation syndrome