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1.
Behav Anal Pract ; 14(1): 208-213, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33732591

ABSTRACT

The present study evaluated the effectiveness of noncontingent reinforcement combined with extinction in the treatment of perseverative speech of an 11-year-old boy with autism spectrum disorder. Following a functional analysis that suggested perseverative speech was maintained by attention, treatment was introduced and consisted of delivering attention on a fixed-time schedule and placing perseverative speech on extinction. The intervention resulted in a 98.5% decrease in perseverative speech, which maintained over a 28-month period.

2.
Liver Int ; 40(5): 1225-1238, 2020 05.
Article in English | MEDLINE | ID: mdl-32141704

ABSTRACT

BACKGROUND AND AIMS: Autophagy is a critical process in cell survival and the maintenance of homeostasis. However, the implementation of therapeutic approaches based on autophagy mechanisms after liver damage is still challenging. METHODS: We used a hepatospecific Atg7-deficient murine model to address this question. RESULTS: We showed that the proliferation and regeneration capacity of Atg7-deficient hepatocytes was impaired. On the one hand, Atg7-deficient hepatocytes showed steady-state hyperproliferation. On the other hand, external triggers such as partial hepatectomy (PHx) or cell transplantation did not induce hepatocellular proliferation or liver repopulation. After PHx, hepatocyte proliferation was strongly decreased, accompanied by high mortality. This increase in mortality could be overcome by pharmacological mTOR inhibition. In accordance with hepatocyte hypoproliferation after damage, Atg7-deficient hepatocytes failed to repopulate the liver in a hepatic injury model. Atg7-deficient mice showed hepatic hypertrophy, transient cellular hypertrophy, and high transaminase levels followed by strong perisinusoidal/pericellular fibrosis with age. Their elevated modified hepatic activity index (mHAI) was almost exclusively due to apoptosis without any inflammation. These parameters were associated with variations in the triglyceride content and compromised lipid droplet formation after PHx. Mechanistically, we also observed a modulation of HGF, PAK4, NOTCH3 and YES1, which are proteins involved in cell cycle regulation. CONCLUSION: We demonstrated the important role of autophagy in the regeneration capacity of hepatocytes. We showed the causative relationship between autophagy and triglycerides that is essential for promoting liver recovery. Finally, pharmacological mTOR inhibition overcame the impact of autophagy deficiency after liver damage and prevented mortality.


Subject(s)
Liver Regeneration , Liver , Animals , Autophagy , Autophagy-Related Protein 7/genetics , Cell Proliferation , Hepatectomy , Hepatocytes , Mice , Mice, Inbred C57BL
3.
Cancer Cell ; 30(2): 308-323, 2016 08 08.
Article in English | MEDLINE | ID: mdl-27478039

ABSTRACT

Hepatocellular carcinoma (HCC) represents a classic example of inflammation-linked cancer. To characterize the role of the immune system in hepatic injury and tumor development, we comparatively studied the extent of liver disease and hepatocarcinogenesis in immunocompromised versus immunocompetent Fah-deficient mice. Strikingly, chronic liver injury and tumor development were markedly suppressed in alymphoid Fah(-/-) mice despite an overall increased mortality. Mechanistically, we show that CD8(+) T cells and lymphotoxin ß are central mediators of HCC formation. Antibody-mediated depletion of CD8(+) T cells as well as pharmacological inhibition of the lymphotoxin-ß receptor markedly delays tumor development in mice with chronic liver injury. Thus, our study unveils distinct functions of the immune system, which are required for liver regeneration, survival, and hepatocarcinogenesis.


Subject(s)
Carcinoma, Hepatocellular/immunology , Liver Diseases/immunology , Liver Neoplasms/immunology , Adaptive Immunity , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Carcinogenesis/immunology , Carcinoma, Hepatocellular/pathology , Humans , Hydrolases/immunology , Liver Diseases/pathology , Liver Neoplasms/pathology , Liver Regeneration/immunology , Lymphotoxin-beta/immunology , Mice
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