43 research outputs found
Inhibition of Specific NF-κB Activity Contributes to the Tumor Suppressor Function of 14-3-3σ in Breast Cancer
14-3-3σ is frequently lost in human breast cancers by genetic deletion or promoter methylation. We have now investigated the involvement of 14-3-3σ in the termination of NF-κB signal in mammary cells and its putative role in cancer relapse and metastasis. Our results show that 14-3-3σ regulates nuclear export of p65-NF-κB following chronic TNFα stimulation. Restoration of 14-3-3σ in breast cancer cells reduces migration capacity and metastatic abilities in vivo. By microarray analysis, we have identified a genetic signature that responds to TNFα in a 14-3-3σ-dependent manner and significantly associates with different breast and other types of cancer. By interrogating public databases, we have found that over-expression of this signature correlates with poor relapse-free survival in breast cancer patients. Finally, screening of 96 human breast tumors showed that NF-κB activation strictly correlates with the absence of 14-3-3σ and it is significantly associated with worse prognosis in the multivariate analysis. Our findings identify a genetic signature that is important for breast cancer prognosis and for future personalized treatments based on NF-κB targeting
Rule-Based Cell Systems Model of Aging using Feedback Loop Motifs Mediated by Stress Responses
Investigating the complex systems dynamics of the aging process requires integration of a broad range of cellular processes describing damage and functional decline co-existing with adaptive and protective regulatory mechanisms. We evolve an integrated generic cell network to represent the connectivity of key cellular mechanisms structured into positive and negative feedback loop motifs centrally important for aging. The conceptual network is casted into a fuzzy-logic, hybrid-intelligent framework based on interaction rules assembled from a priori knowledge. Based upon a classical homeostatic representation of cellular energy metabolism, we first demonstrate how positive-feedback loops accelerate damage and decline consistent with a vicious cycle. This model is iteratively extended towards an adaptive response model by incorporating protective negative-feedback loop circuits. Time-lapse simulations of the adaptive response model uncover how transcriptional and translational changes, mediated by stress sensors NF-κB and mTOR, counteract accumulating damage and dysfunction by modulating mitochondrial respiration, metabolic fluxes, biosynthesis, and autophagy, crucial for cellular survival. The model allows consideration of lifespan optimization scenarios with respect to fitness criteria using a sensitivity analysis. Our work establishes a novel extendable and scalable computational approach capable to connect tractable molecular mechanisms with cellular network dynamics underlying the emerging aging phenotype
Health sector spending and spending on HIV/AIDS, tuberculosis, and malaria, and development assistance for health: progress towards Sustainable Development Goal 3
Background: Sustainable Development Goal (SDG) 3 aims to “ensure healthy lives and promote well-being for all at all
ages”. While a substantial effort has been made to quantify progress towards SDG3, less research has focused on
tracking spending towards this goal. We used spending estimates to measure progress in financing the priority areas
of SDG3, examine the association between outcomes and financing, and identify where resource gains are most
needed to achieve the SDG3 indicators for which data are available.
Methods: We estimated domestic health spending, disaggregated by source (government, out-of-pocket, and prepaid
private) from 1995 to 2017 for 195 countries and territories. For disease-specific health spending, we estimated
spending for HIV/AIDS and tuberculosis for 135 low-income and middle-income countries, and malaria in
106 malaria-endemic countries, from 2000 to 2017. We also estimated development assistance for health (DAH) from
1990 to 2019, by source, disbursing development agency, recipient, and health focus area, including DAH for
pandemic preparedness. Finally, we estimated future health spending for 195 countries and territories from 2018 until
2030. We report all spending estimates in inflation-adjusted 2019 US7·9 trillion (95% uncertainty interval 7·8–8·0) in 2017 and is expected to increase to 20·2 billion
(17·0–25·0) and on tuberculosis it was 5·1 billion (4·9–5·4). Development assistance for health was 374 million of DAH was provided
for pandemic preparedness, less than 1% of DAH. Although spending has increased across HIV/AIDS, tuberculosis,
and malaria since 2015, spending has not increased in all countries, and outcomes in terms of prevalence, incidence,
and per-capita spending have been mixed. The proportion of health spending from pooled sources is expected to
increase from 81·6% (81·6–81·7) in 2015 to 83·1% (82·8–83·3) in 2030.
Interpretation: Health spending on SDG3 priority areas has increased, but not in all countries, and progress towards
meeting the SDG3 targets has been mixed and has varied by country and by target. The evidence on the scale-up of
spending and improvements in health outcomes suggest a nuanced relationship, such that increases in spending do
not always results in improvements in outcomes. Although countries will probably need more resources to achieve
SDG3, other constraints in the broader health system such as inefficient allocation of resources across interventions
and populations, weak governance systems, human resource shortages, and drug shortages, will also need to be
addressed.
Funding: The Bill & Melinda Gates Foundatio
Identification and preliminary structure-activity relationship studies of 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-ones that induce differentiation of acute myeloid leukemia cells in vitro
Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional cytotoxic chemotherapy, but known agents lack efficacy in genetically distinct patient populations. Previously, we established a phenotypic screen to identify small molecules that could stimulate differentiation in a range of AML cell lines. Utilising this strategy, a 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one hit compound was identified. Herein, we report the hit validation in vitro, structure-activity relationship (SAR) studies and the pharmacokinetic profiles for selected compounds
A phenotypic screen identifies a compound series that induces differentiation of acute myeloid leukemia cells in vitro and shows antitumor effects in vivo
Induction of differentiation is a promising therapeutic strategy against acute myeloid leukemia. However, current differentiation therapies are effective only to specific patient populations. To identify novel differentiation agents with wider efficacy, we developed a phenotypic high-throughput screen with a range of genetically diverse cell lines. From the resulting hits, one chemical scaffold was optimized in terms of activity and physicochemical properties to yield OXS007417, a proof-of-concept tool compound, which was also able to decrease tumor volume in a murine in vivo xenograft model
A tubulin binding molecule drives differentiation of acute myeloid leukemia cells
Despite much progress in developing better drugs, many patients with acute myeloid leukemia (AML) still die within a year of diagnosis. This is partly because it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Overcoming this block should allow for the identification of therapies that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify compounds that stimulate differentiation in genetically diverse AML cell lines. Lead compounds were shown to decrease tumor burden and to increase survival in vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a function for tubulin disruptors in causing differentiation of AML cells