Stress-induced cardiomyocyte apoptosis plays an important role in the pathogenesis of a variety of cardiovascular diseases. Our early studies showed that HSP70 effectively inhibited apoptosis, but the underlying mechanism remained unclear. Fas-associated factor 1 (FAF1) is a member of the Fas death-inducing signaling complex (Fas-DISC) that acts upstream of caspase-8. We investigated the interactions among FAF1, HSP70, and FAS in stressed cardiomyocytes to elucidate the protective mechanism of HSP70. FAS and caspase-3/8 activity was higher in cardiomyocytes undergoing stress-induced apoptosis in restraint-stressed rats compared with cardiomyocytes in non-stressed rats, which indicated that the Fas signaling pathway was activated after restraint stress. Geranylgeranylacetone (GGA) induced an increase in HSP70 expression, which reduced stress-induced apoptosis. Additionally, overexpression of HSP70 via transfection with the pEGFP-rHSP70 plasmid attenuated norepinephrine (NE)-induced apoptosis. FAF1 expression increased during stressinduced apoptosis, and overexpression of FAF1 exacerbated NE-induced apoptosis. We also found that HSP70 interacted with FAF1. Overexpression of HSP70 inhibited the binding of FAF1 to FAS in H9C2 cells, which indicated that HSP70 suppressed NE-induced apoptosis by competitively binding to FAF1. An N-terminal deletion mutant of HSP70 (HSP70-△N) was unable to interact with FAF1. After HSP70-△N was transfected into H9C2 cells, the cells were unable to attenuate the NE-induced increases in caspase-8 and apoptosis. These results indicate that the 1-120 sequence of HSP70 binds to FAF1, which alters the interactions between FAS and FAF1 and inhibits the activation of the Fas signaling pathway and apoptosis.

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Health insurance costs across the world have increased alarmingly in recent years. A major cause of this increase are payment errors made by the insurance companies while processing claims. These errors often result in extra administrative effort to re-process (or rework) the claim which accounts for up to 30% of the administrative staff in a typical health insurer. We describe a system that helps reduce these errors using machine learning techniques by predicting claims that will need to be reworked, generating explanations to help the auditors correct these claims, and experiment with feature selection, concept drift, and active learning to collect feedback from the auditors to improve over time. We describe our framework, problem formulation, evaluation metrics, and experimental results on claims data from a large US health insurer. We show that our system results in an order of magnitude better precision (hit rate) over existing approaches which is accurate enough to potentially result in over $15-25 million in savings for a typical insurer. We also describe interesting research problems in this domain as well as design choices made to make the system easily deployable across health insurance companies.

Cancer stem cell (CSC) is thought to be the major cause of radio-resistance and relapse post radiotherapy (RT). Recently ultra-high dose rate “FLASH-RT” evokes great interest for its decreasing normal tissue damages while maintaining tumor responses compared with conventional dose rate RT. However, the killing effect and mechanism of FLASH irradiation (FLASH-IR) on CSC and normal cancer cell are still unclear. Presently the radiation induced death profile of CSC and normal cancer cell were studied. Cells were irradiated with FLASH-IR (∼109 Gy/s) at the dose of 6–9 Gy via laser-accelerated nanosecond particles. Then the ratio of apoptosis, pyroptosis and necrosis were determined. The results showed that FLASH-IR can induce apoptosis, pyroptosis and necrosis in both CSC and normal cancer cell with different ratios. And CSC was more resistant to radiation than normal cancer cell under FLASH-IR. Further experiments tracing lysosome and autophagy showed that CSCs had higher levels of lysosome and autophagy. Taken together, our results suggested that the radio-resistance of CSC may associate with the increase of lysosome-mediated autophagy, and the decrease of apoptosis, necrosis and pyroptosis. To our limited knowledge, this is the first report shedding light on the killing effects and death pathways of CSC and normal cancer cell under FLASH-IR. By clarifying the death pathways of CSC and normal cancer cell under FLASH-IR, it may help us improve the understanding of the radio-resistance of CSC and thus help to optimize the future clinical FLASH treatment plan.

Fibrosis is an important, structurally damaging event that occurs in pathological cardiac remodeling, leading to cardiac dysfunction. BNIP3L is up-regulated in pressure overload-induced heart failure and has been reported to play an important role in cardiomyocyte apoptosis; however, its involvement in cardiac fibroblasts (CFs) remains unknown. We prove for the first time that the expression of BNIP3L is significantly increased in the CFs of rats undergoing pressure overload-induced heart failure. Furthermore, this increased BNIP3L expression was confirmed in cultured neonatal rat CFs undergoing proliferation and extracellular matrix (ECM) protein over-expression that was induced by norepinephrine (NE). The overexpression or suppression of BNIP3L promoted or inhibited NE-induced proliferation and ECM expression in CFs, respectively. In addition, [Ca2+]i, transforming growth factor beta (TGF-β) and the nuclear accumulation of Smad2/3 were successively increased when BNIP3L was overexpressed and reduced when BNIP3L was inhibited. Furthermore, the down-regulation of TGF-β by TGF-β-siRNA attenuated the increase of BNIP3L-induced fibronectin expression. We also demonstrated that the increase of BNIP3L in CFs was regulated by NE-AR-PKC pathway in vitro and in vivo. These results reveal that BNIP3L is a novel mediator of pressure overload-induced cardiac fibrosis through the [Ca2+]i-TGF-β-Smad2/3 pathway in CFs.