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  • 1
  • 2
    Abstract: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4(+) but not CD8(+) T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4(+) T lymphocytes have greater mitochondrial mass than CD8(+) T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4(+) T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4(+) T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance.
    Type of Publication: Journal article published
    PubMed ID: 26934227
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  • 3
    Abstract: Oncogene-induced senescence causes hepatocytes to secrete cytokines, which induce their immune-mediated clearance to prevent tumor initiation, a process termed "senescence surveillance." However, senescent hepatocytes give rise to hepatocellular carcinomas (HCCs), if the senescence program is bypassed or if senescent cells are not cleared. Here, we show context-specific roles for CCR2+ myeloid cells in liver cancer. Senescence surveillance requires the recruitment and maturation of CCR2+ myeloid cells, and CCR2 ablation caused outgrowth of HCC. In contrast, HCC cells block the maturation of recruited myeloid precursors, which, through NK cell inhibition, promote growth of murine HCC and worsen the prognosis and survival of human HCC patients. Thus, while senescent hepatocyte-secreted chemokines suppress liver cancer initiation, they may accelerate the growth of fully established HCC.
    Type of Publication: Journal article published
    PubMed ID: 27728804
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  • 4
    ISSN: 1432-1106
    Keywords: Key words Corrective saccades ; Latency ; Saccadic eye movements ; Saccadic suppression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  This study investigates how visually guided saccades and subsequent corrective saccades are affected by a secondary target step occurring at different times during the primary saccade. Eye movements of human subjects were measured by means of a differential infrared light reflection technique while the subjects performed visually guided saccades to a laser spot in darkness. The target was stepped backward or onward during the targeting saccade. While the intrasaccadic target step did not influence gain, peak velocity or skewness of the primary saccade, it had a significant effect on the subsequent corrective saccade when the secondary target step occurred during the deceleration phase of the primary saccade: the latency of the corrective saccade was significantly increased compared with the one performed under the single-step control condition. This increase also occurred when single target steps were presented randomly intermixed with backward and onward double target steps and even between selected sub-samples of saccades with identical postsaccadic visual error. If the target step occurred early during the primary saccade, the latency of the corrective saccade was not changed. This indicates that visual information sampled during the deceleration phase of a saccade can lead to a cancellation of the normal trigger mode of corrective saccades.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1433-0407
    Keywords: Schlüsselwörter Anteriorer Bogengang ; Oszillopsie ; Perilymphfistel ; Schwindel ; Tullio-Phänomen ; Key words Anterior semicircular canal ; Perilymphatic fistula ; Tullio's phenomenon ; Vertigo ; Vestibular system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary In 1998 Minor et al. described a new variant of perilymphatic fistula: the “superior canal dehiscence syndrome”. This syndrome is clinically characterized by recurrent attacks of vertigo and oscillopsia induced by loud noises or stimuli that result in changes in intracranial or middle ear pressure. It is caused by a dehiscence of bone overlying the superior (anterior) semicircular canal. Due to this dehiscence, a third, mobile window (in addition to the round and oval windows) is formed, and changes in pressure are pathologically transduced to the anterior semicircular canal. Although the superior canal dehiscence syndrome is not a rare condition, no other cases have yet been reported. Therefore, we describe a typical patient who suffered for many years from recurrent attacks of vertigo and oscillopsia induced by coughing and Valsalva's maneuvers. High resolution temporal bone CT scan showed a defect in the bone overlying the left anterior semicircular canal. Three-dimensional eye movement recordings using the search coil technique and subsequent vector analysis demonstrated that the eye movements were induced by excitation of the left anterior semicircular canal. We conclude that superior canal dehiscence syndrome is an important differential diagnosis in patients suffering from symptoms of a perilymphatic fistula, especially since it can be successfully treated by “plugging” of the affected semicircular canal. Such patients are thus spared unnecessary surgery of the middle ear.
    Notes: Zusammenfassung Minor et al. beschrieben 1998 eine neue Form der Perilymphfistel: die “innere Labyrinthfistel des anterioren Bogengangs”. Pathologisch-anatomisch liegt dieser ein knöcherner Defekt im Bereich des anterioren Bogengangs (zum Epiduralraum hin) zugrunde. Pathophysiologisch führt der Knochendefekt zu einem dritten mobilen Fenster (neben dem runden und ovalen) und so zu einer pathologischen Druckübertragung zum Perilymphraum. Obwohl die innere Fistel offenbar nicht selten ist, liegen zu diesem neuen differentialdiagnostisch und therapeutisch wichtigen Krankheitsbild bislang keine weiteren Veröffentlichungen vor. Deshalb beschreiben wir exemplarisch einen typischen Patienten mit seit Jahren bestehenden, durch Husten und Pressen ausgelösten Schwindelattacken, bei dem sich im hochauflösenden CT ein Knochendefekt im oberen Anteil des linken anterioren Bogengangs fand. Übereinstimmend damit konnte mittels dreidimensionaler Analyse der durch Druckänderungen induzierten Augenbewegungen nachgewiesen werden, dass diese tatsächlich auf einer Erregung des linken anterioren Bogengangs beruhen. Bei Patienten mit den Symptomen einer Perilymphfistel sollte an die Möglichkeit einer inneren Labyrinthfistel gedacht werden, insbesondere um ihnen eine unnötige Operation im Bereich des Mittelohres zu ersparen und sie statt dessen ggf. einer angemessenen operativen Behandlung (sog. “Plugging”, d. h. Obliteration des anterioren Bogengangs) zuführen zu können.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1433-8491
    Keywords: Key words Saccadic velocity ; Internally guided ; saccades ; Visually guided saccades ; Neuroleptics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Saccadic eye movements were elicited in 30 schizophrenic patients before and in 17 of these 30 during antipsychotic treatment with neuroleptics, and compared with those of 12 age-matched controls under three different conditions: (a) the gap paradigm, which tests the visually triggered and visually guided saccades; (b) the anti-task paradigm, which tests the internally guided, visually triggered saccades; and (c) the memory paradigm, which tests the internally triggered and guided saccades. Eye movements were recorded by DC electro-oculography, and the peak eye velocities for the different saccades were calculated. We found that antipsychotic treatment with neuroleptics reduces the peak saccadic eye velocity. This effect is larger for internally guided saccades than for externally triggered and guided eye movements. The saccadic velocity of the unmedicated schizophrenic patients did not differ from that of the controls. Since patients with diseases of the basal ganglia primarily show abnormalities of the internally guided and triggered saccades, our findings indicate that neuroleptics influence the oculomotor loop through the basal ganglia and that this loop, by means of neuroleptic influence on the brainstem saccadic burst generator, also influences the peak velocity of the internally guided saccades. This contradicts the current idea of the role of the cortical input to the brainstem saccadic burst generator, which is thought to not be involved in the determination of saccadic velocity.
    Type of Medium: Electronic Resource
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  • 7
    Publication Date: 2016-03-05
    Description: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4(+) but not CD8(+) T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4(+) T lymphocytes have greater mitochondrial mass than CD8(+) T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4(+) T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4(+) T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786464/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786464/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ma, Chi -- Kesarwala, Aparna H -- Eggert, Tobias -- Medina-Echeverz, Jose -- Kleiner, David E -- Jin, Ping -- Stroncek, David F -- Terabe, Masaki -- Kapoor, Veena -- ElGindi, Mei -- Han, Miaojun -- Thornton, Angela M -- Zhang, Haibo -- Egger, Michele -- Luo, Ji -- Felsher, Dean W -- McVicar, Daniel W -- Weber, Achim -- Heikenwalder, Mathias -- Greten, Tim F -- ZIA BC011345-06/Intramural NIH HHS/ -- ZIABC011303/PHS HHS/ -- England -- Nature. 2016 Mar 10;531(7593):253-7. doi: 10.1038/nature16969. Epub 2016 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Institute of Surgical Pathology, University and University Hospital Zurich, Zurich 8091, Switzerland. ; Division of Oncology, Department of Medicine and Pathology, Stanford University, California 94305, USA. ; Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland 21702, USA. ; Institute of Virology, Technische Universitat Munchen/Helmholtz Zentrum Munchen, Munich 81675, Germany. ; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934227" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CD4-Positive T-Lymphocytes/immunology/metabolism/*pathology ; CD8-Positive T-Lymphocytes/immunology/pathology ; *Carcinogenesis/immunology/pathology ; Carcinoma, Hepatocellular/*immunology/metabolism/*pathology ; Case-Control Studies ; Choline/metabolism ; Diet ; Disease Models, Animal ; Genes, myc ; Hepatocytes/metabolism/pathology ; Humans ; Linoleic Acid/metabolism ; Lipid Metabolism ; Liver/immunology/pathology ; Liver Neoplasms/*immunology/metabolism/*pathology ; Male ; Methionine/deficiency ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism/pathology ; Non-alcoholic Fatty Liver Disease/*immunology/metabolism/pathology ; Oxidative Stress ; Reactive Oxygen Species/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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