Serine residues 1177/78/82 of the insulin receptor are required for substrate phosphorylation but not autophosphorylation

Serine residues of the human insulin receptor (HIR) may be phosphorylated and negatively regulate the insulin signal. We studied the impact of 16 serine residues in HIR by mutation to alanine and co-overexpression in human embryonic kidney (HEK) 293 cells together with the docking proteins insulin receptor substrate (IRS)-1, IRS-2, or (SHC) Src homologous and collagen-like. As a control, IRS-1 was also cotransfected with an HIR with a juxtamembrane deletion (HIR delta JM) and therefore not containing the domain required for interaction with IRS-1. Coexpression of HIR with IRS-1, IRS-2, and SHC strongly enhanced tyrosine phosphorylation of these proteins. A similar increase in tyrosine phosphorylation was observed in cells overexpressing IRS-1, IRS-2, or SHC together with all HIR mutants except HIR delta JM and a mutant carrying exchanges of serines 1177, 1178, and 1182 to alanine (HIR1177/78/82), although this mutant showed normal autophosphorylation. Analysis of total cell lysates with anti-phosphotyrosine antibodies showed that in addition to the overexpressed substrates, other cellular proteins displayed reduced levels of tyrosine phosphorylation in these cells. To study consequences for phosphatidylinositol 3-kinase (PI 3-kinase) activation, we established stable NIH3T3 fibroblast cell lines overexpressing wild-type HIR, HIR1177/78/82, and other HIR mutants as the control. Again, HIR1177/78/82 showed normal autophosphorylation but showed a clear decrease in tyrosine phosphorylation of endogenous IRS-1 and activation of PI 3-kinase. This decrease in kinase activity also occurred in an in vitro kinase assay towards recombinant IRS-1. Finally, we performed a separation of the phosphopeptides by high-performance liquid chromatography and could not detect any differences in the profiles of HIR and HIR1177/78/82. In conclusion, we have defined a region in HIR that is important for substrate phosphorylation but not autophosphorylation. Therefore, this mutant may provide new insights into the mechanism of kinase activation and substrate phosphorylation.

Partial volume correction incorporating Rb-82 positron range for quantitative myocardial perfusion PET based on systolic-diastolic activity ratios and phantom measurements.

BACKGROUND: Quantitative myocardial PET perfusion imaging requires partial volume corrections. METHODS: Patients underwent ECG-gated, rest-dipyridamole, myocardial perfusion PET using Rb-82 decay corrected in Bq/cc for diastolic, systolic, and combined whole cycle ungated images. Diastolic partial volume correction relative to systole was determined from the systolic/diastolic activity ratio, systolic partial volume correction from phantom dimensions comparable to systolic LV wall thicknesses and whole heart cycle partial volume correction for ungated images from fractional systolic-diastolic duration for systolic and diastolic partial volume corrections. RESULTS: For 264 PET perfusion images from 159 patients (105 rest-stress image pairs, 54 individual rest or stress images), average resting diastolic partial volume correction relative to systole was 1.14 ± 0.04, independent of heart rate and within ±1.8% of stress images (1.16 ± 0.04). Diastolic partial volume corrections combined with those for phantom dimensions comparable to systolic LV wall thickness gave an average whole heart cycle partial volume correction for ungated images of 1.23 for Rb-82 compared to 1.14 if positron range were negligible as for F-18. CONCLUSION: Quantitative myocardial PET perfusion imaging requires partial volume correction, herein demonstrated clinically from systolic/diastolic absolute activity ratios combined with phantom data accounting for Rb-82 positron range.

The Kabbalah : its doctrines, development and literature : (repr. verbatim from the first ed. which cont. pp. 1-82 entitles "The Essenes")

by Christian D. Ginsburg

Bibliotheca geographica Palaestinae : chronologisches Verzeichnis der auf die Geographie des Heiligen Landes bezüglichen Literatur von 333 bis 1878 ; und Versuch einer Cartographie

hrsg. von Reinhold Röhricht

Ms. hebr. oct. 82 - Sefer ha-mitsṿot

Vorbesitzer: Eljāqīm Carmoly; Abraham Merzbacher

Ms. Barth. 82 - Compendium theologicae veritatis

Vorbesitzer: Bartholomaeusstift Frankfurt am Main

An die Urwähler des 82. Bezirks: Wir unterzeichnete Urwähler des 82. Bezirks erblicken in der constitutionellen Monarchie ...

Welsch (Projektbearbeiter): Appell von 50 Urwählern des Berliner 82. Bezirks, nur solche Wahlmänner zu wählen, die zur konstitutionellen Monarchie und zur Verfassung vom 5. Dezember 1848 stehen. Letztere ist aufgrund der Möglichkeit der Revision nicht unbedingt oktroyiert zu nennen.

Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database

AbstractBackground It is not easy to overview pending phase 3 trials on prostate cancer (PCa), and awareness of these trials would benefit clinicians. Objective To identify all phase 3 trials on {PCa} registered in the ClinicalTrials.gov database with pending results. Design and setting On September 29, 2014, a database was established from the records for 175 538 clinical trials registered on ClinicalTrials.gov. A search of this database for the substring “prostat” identified 2951 prostate trials. Phase 3 trials accounted for 441 studies, of which 333 concerned only PCa. We selected only ongoing or completed trials with pending results, that is, for which the primary endpoint had not been published in a peer-reviewed medical journal. Results and limitations We identified 123 phase 3 trials with pending results. Trials were conducted predominantly in North America (n = 63; 51) and Europe (n = 47; 38). The majority were on nonmetastatic disease (n = 82; 67), with 37 (30) on metastatic disease and four trials (3) including both. In terms of intervention, systemic treatment was most commonly tested (n = 71; 58), followed by local treatment 34 (28), and both systemic and local treatment (n = 11; 9), with seven (6) trials not classifiable. The 71 trials on systemic treatment included androgen deprivation therapy (n = 34; 48), chemotherapy (n = 15; 21), immunotherapy (n = 9; 13), other systemic drugs (n = 9; 13), radiopharmaceuticals (n = 2; 3), and combinations (n = 2; 3). Local treatments tested included radiation therapy (n = 27; 79), surgery (n = 5; 15), and both (n = 2; 2). A limitation is that not every clinical trial is registered on ClinicalTrials.gov. Conclusion There are many {PCa} phase 3 trials with pending results, most of which address questions regarding systemic treatments for both nonmetastatic and metastatic disease. Radiation therapy and androgen deprivation therapy are the interventions most commonly tested for local and systemic treatment, respectively. Patient summary This report describes all phase 3 trials on prostate cancer registered in the ClinicalTrials.gov database with pending results. Most of these trials address questions regarding systemic treatments for both nonmetastatic and metastatic disease. Radiation therapy and androgen deprivation therapy are the interventions most commonly tested for local and systemic treatment, respectively.

Na 1 Nachlass Max Horkheimer, 58 - Korrespondenzen u.a. mit Betty Drury (p. I 27, 186-333)

5 Briefe zwischen Konrad Wittwer und Max Horkheimer, 1936, 1938, 1939; 1 Brief von Max Horkheimer an Joseph Wohl, 18.08.1934; 1 Brief von Max Horkheimer an Hedwig Wollenberger, 25.02.1941; 2 Briefe zwischen Richard Wolf und Max Horkheimer, 22.10.1938, 07.11.1938; 2 Briefe zwischen Martha Wolfenstein und Max Horkheimer, 11.10.1937, 19.10.1937; 1 Brief von Clemy Wolff an Leo Löwenthal, 05.03.1941; 2 Briefe zwischen Ilse Wolff und Max Horkheimer, 29.08.1937, 03.09.1937; 1 Brief von Max Horkheimer an Howard Woolston, 25.03.1941; 1 Einladung von der Women's Conference, 1935; 1 Brief von Max Horkheimer an die Women's Conference, 15.03.1935; 1 Brief von der World Foundation an Max Horkheimer, 26.11.1937; 2 Briefe vom World Jewish Congress an Max Horkheimer, 1942, 1945; 1 Brief von Max Horkheimer an Francis Henry Russel, 28.09.1942; 1 Brief von Max Horkheimer an Dr. Opie, 28.09.1942; 1 Brief der Württembergische Hypothekenbank an Max Horkheimer, 24.12.1930; 12 Briefe zwischen Rösle Wuestholz und Max Horkheimer, 1935-1937, 1939; 1 Brief von Max Horkheimer an Frida Wunderlich, 22.11.1937; 1 Brief von Max Horkheimer an die Yale University Library, 22.12.1938; 2 Briefe zwischen Owen D. Young und Max Horkheimer, 22.04.1940, April 1940; 3 Briefe zwischen Hans Zeisel und Max Horkheimer, 21.07.1941, 1941, 1944; 2 Briefe zwischen der Zentrale Hilfsstelle für deutsche Flüchtlingskinder Prag und Max Horkheimer, 01.03.1938, 25.04.1938; 6 Briefe zwischen Gregory Zilboorg und Max Horkheimer, 1939; 16 Briefe und Beilage an Max Horkheimer und F. Pollock von Edgar Zilsel, 1939-1942; 1 Brief vom Social Science Research Counsil an Edgar Zilsel, 01.04.1940; 1 Brief von The Rockefeller Foundation an Edgar Zilsel, 20.06.1939; 9 Briefe und Beilage von Max Horkheimer und F. Pollock an Edgar Zilsel, 1939-1942 sowie Briefwechsel mit Betty Drury; 10 Briefe zwischen The Rockefeller Foundation und Max Horkheimer, 1939-1940; 1 Brief von Max Horkheimer an Edgar Zilsel, 20.06.1939; 12 Briefe zwischen Betty Drury und F. Pollock, 1939-1940; 7 Briefe zwischen Alexander Zinnemann und Max Horkheimer, 1936;