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

Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial

BACKGROUND Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. METHODS This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. FINDINGS From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7·0 years (IQR 5·2-8·7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0·78, 95% CI 0·56-1·08; p=0·13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0·54, 95% CI 0·4-0·73, p<0·0001), with 5-year progression-free survival of 47·6% (95% CI 38·8-55·9) in the immediate treatment group and 31·8% (24·2-39·6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. INTERPRETATION Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. FUNDING Lilly, Canadian Cancer Society Research.

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.

Na 50 Nachlass Arthur Schopenhauer - 'Schopenhauer-Archiv', 559 - Entgegnung von Abraham Ludwig Muhl auf das abgelehnte Vergleichsangebot

u.a.: Friedrich Soermans;

Na 50 Nachlass Arthur Schopenhauer - 'Schopenhauer-Archiv', 82 - Hervorhebung der besonderen Freundschaft mit Schopenhauer

u.a.: Marie;

Na 1 Nachlass Max Horkheimer, 291 - Korrespondenzen u.a. mit Heinz Joachim Heydorn (p. V 82, 119-246)

3 Briefe zwischen Graf Lazy Henckel von Donnersmarck und Max Horkheimer, 1968; 2 Briefe zwischen Gräfin Nina Henckel von Donnersmarck und Max Horkheimer, 1968; 4 Briefe zwischen der Sängerin Carla Henius und Max Horkheimer, 1970-1971; 1 Brief an K. H. Hennings von Max Horkheimer, 1967; 4 Briefe zwischen Professor Wilhelm Hennis und Max Horkheimer, 1971; 1 Brief an Professor Dieter Henrich von Max Horkheimer, 1964; 2 Briefe zwischen Caroline Hergert und Max Horkheimer, 1970; 1 Brief von Professor Fred Herman an Max Horkheimer, 1959; 2 Briefe zwischen der Fachschülerin Dora Herrmann und Max Horkheimer, 1972; 2 Briefe zwischen Professor Franz Herrmann und Max Horkheimer, 1970; 6 Briefe zwischen Dr. phil. Gert-Julius Herrmann und Max Horkheimer, 1968; 2 Briefe zwischen Dipl. Kfm. Dr. Dr. Otto O. Herz und Max Horkheimer, 1969; 4 Briefe zwischen Professor und Museumsdirektor Erich Herzog und Max Horkheimer, 1970; 2 Briefe zwischen Hans Eberhard Hess und Max Horkheimer, 1970; 16 Briefe zwischen Professor Eugen Hess-Baer und Max Horkheimer, 1966-1971; 3 Briefe zwischen Karl Hess und Max Horkheimer, 1969-1971; 1 Drucksache von Pfarrer Walter Hess, 1971; 6 Briefe zwischen dem Bankier Walter Hesselbach und Max Horkheimer, 1971-1973; Drucksachen vom Hessischen Kreis, 1968; Briefe zwischen dem Hessischen Landesmuseum Darmstadt und Max Horkheimer, 1969; 25 Briefe zwischen Professor Heinz Joachim Heydorn und Max Horkheimer, 1965-1973; 2 Briefe zwischen Dr. Karl Heymann und Max Horkheimer, 1970; 1 Brief an den Hippokrates-Verlag von Max Horkheimer, 1971; 9 Briefe zwischen Walter Hirschmann und Max Horkheimer, 1969-1971;