The metastatic T-cell hybridoma antigen/P-selectin glycoprotein ligand 1 is required for hematogenous metastasis of lymphomas

Using variants of the murine BW5147 lymphoma cell-line, we have previously identified 3 monoclonal antibodies (MAbs) that discriminate between metastatic and nonmetastatic BW5147-derived T-cell hybridomas and lymphomas, as well as BW5147-unrelated T-lymphomas. These MAbs were reported to recognize an identical membrane-associated sialoglycoprotein, termed "metastatic T-cell hybridoma antigen" (MTH-Ag). Here, we document that the expression pattern of the MTH-Ag on metastatic and nonmetastatic BW5147 variants correlates with that of the P-selectin glycoprotein ligand 1 (PSGL-1), a sialomucin involved in leukocyte recruitment to sites of inflammation. Moreover, the MAbs against the MTH-Ag recognize PSGL-1 when it is transfected in MTH-Ag-negative BW5147 variants, suggesting that the MTH-Ag is PSGL-1. Overexpression of MTH-Ag/PSGL-1 in MTH-Ag-negative BW5147 variants did not affect their in vivo malignancy. Yet, down-regulation of MTH-Ag/PSGL-1 expression on metastatic, MTH-Ag-positive BW5147 variants, using an RNA interference (RNAi) approach, resulted, in a dose-dependent manner, in a significant reduction of liver and spleen colonization and a delay in mortality of the recipient mice upon intravenous inoculation. Collectively, these results demonstrate that, although MTH-Ag/PSGL-1 overexpression alone may not be sufficient for successful dissemination and organ colonization, MTH-Ag/PSGL-1 plays a critical role in hematogenous metastasis of lymphoid cancer cells.

Na 1 Nachlass Max Horkheimer, 45 - Korrespondenzen u.a. mit der Familie Rabinowitsch, Friedrich Pollock und Franz Neumann (p. I 21, A, 1-218)

37 Briefe zwischen Fritz Rabinowitsch, Gregor Rabinowitsch, Fred Roberts und Max Horkheimer, 1936-1943; 14 Briefe und Beilagen zwischen Finley Parker, Benjamin Parker und dem American General Consulat, 1937-1939; 4 Brief zwischen dem National Council of Jewish Women New York und Max Horkheimer, 1937; 31 Briefe und Beilagen zwischen Finley Parker, Benjamin Parker und Max Horkheimer, 1937-1939; 7 Briefe zwischen Franz L. Neumann und Finley Parker, Benjamin Parker, 09.10.1937, 1937; 2 Briefe zwischen dem American Conulat, General und dem National Council of Jewish Women, 27.07.1937, 16.08.1937; 1 Brief von Finley und Benjamin Parker an Gregor Rabinowitsch, 22.10.1937; 3 Briefe von Max Horkheimer an das United States Consulate Berlin, 1937; 1 Brief von Finley und Benjamin Parker an Hans-Heinrich Schulz, 21.09.1937; 1 Brief von Finley und Benjamin Parker an Eberhard Roethe, 21.09.1937; 6 Briefe zwischen Friedrich Pollock und Max Horkheimer, 1937-1943; 2 Briefe zwischen dem Schweizerischer Buchhändlerverein und Max Horkheimer, 31.07.1937, 10.09.1937; 2 Briefe zwischen Robert Hilb und Max Horkheimer, 07.09.1937; 2 Briefe zwischen Franz Neumann und Max Horkheimer, 29.08.1937, 31.08.1937; 11 Briefe zwischen Alexander Farquharson und Max Horkheimer, 1937; 1 Brief von Girsberger an Max Horkheimer, 29.08.1937; 1 Brief von Abner J. Rubien an Max Horkheimer, 29.07.1937; 1 Brief von Brill an Max Horkheimer, 29.07.1937; 2 Briefe zwischen Otto Nathan und Max Horkheimer, 28.07.1937, 25.04.1939; 5 Briefe zwischen dem Germany Emergency Committee London und Max Horkheimer, 1937; 2 Briefe von der National City Bank New York an das American Consul, New York, 1937; 1 Brief von John G. Jenkins an Paul F. Lazarsfeld, 05.04.1937; 3 Briefe zwischen Frank H. Bowles und Max Horkheimer, 23.03.1937, 1937;

Na 1 Nachlass Max Horkheimer, 646 - "Studien über Autorität und Vorurteil" (p. IX 27a. Band 1)

Gekürzte deutsche Fassung der Bände I-III und V der "Studies in Prejudice", editiert von Max Horkheimer und S. H. Flowerman, New York ,1949/50;

Na 1 Nachlass Max Horkheimer, 608 - Vorlesung: "Geschichte der neueren Philosophie" 1 (p. VIII 7, 2a.1 - VIII 7, 2a.4)

Vorlesungsskript, Typoskript mit eigenhändigen Korrekturen, Heft 1-4 (GS 9, S.11-480);

Na 1 Nachlass Max Horkheimer, 565 - Korrespondenzen u.a. mit Herbert Marcuse und Leo Löwenthal (p. VI 27 A, 1-292)

183 Briefe zwischen Herbert Marcuse und Max Horkheimer; 6 Briefe zwischen Margot von Mendelssohn und Herbert Marcuse, 1942 - 1949; 1 Brief von Friedrich Pollock an Max Horkheimer, 20.04.1943; 1 Brief von dem Office of Strategic Services (Washington) an Herbert Marcuse, 07.12.1942; 1 Brief von dem Office of War Information (Washington) an Herbert Marcuse, 16.11.1942; 3 Briefe zwischen Herbert Marcuse und Francis K. Ballaine, Januar 1942; 1 Brief an Friedrich Pollock von Herbert Marcuse, 18.07.1949; 1 Brief von Herbert Marcuse an Leo Löwenthal, 11.04.1949;

Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury

Substance P, acting via the neurokinin 1 receptor (NK1R), plays an important role in mediating a variety of inflammatory processes. However, its role in acute pancreatitis has not been previously described. We have found that, in normal mice, substance P levels in the pancreas and pancreatic acinar cell expression of NK1R are both increased during secretagogue-induced experimental pancreatitis. To evaluate the role of substance P, pancreatitis was induced in mice that genetically lack NK1R by administration of 12 hourly injections of a supramaximally stimulating dose of the secretagogue caerulein. During pancreatitis, the magnitude of hyperamylasemia, hyperlipasemia, neutrophil sequestration in the pancreas, and pancreatic acinar cell necrosis were significantly reduced in NK1R−/− mice when compared with wild-type NK1R+/+ animals. Similarly, pancreatitis-associated lung injury, as characterized by intrapulmonary sequestration of neutrophils and increased pulmonary microvascular permeability, was reduced in NK1R−/− animals. These effects of NK1R deletion indicate that substance P, acting via NK1R, plays an important proinflammatory role in regulating the severity of acute pancreatitis and pancreatitis-associated lung injury.

Tyrosine replacement in P-selectin glycoprotein ligand-1 affects distinct kinetic and mechanical properties of bonds with P- and L-selectin

Selectins are adhesion molecules that initiate tethering and rolling of leukocytes on the vessel wall. Rolling requires rapid formation and breakage of selectin–ligand bonds that must have mechanical strength to resist premature dissociation by the forces applied in shear flow. P- and L-selectin bind to the N-terminal region of P-selectin glycoprotein ligand-1 (PSGL-1), a mucin on leukocytes. To define determinants on PSGL-1 that contribute to the kinetic and mechanical properties of bonds with selectins, we compared rolling of transfected preB cells expressing P- or L-selectin on transfected cell monolayers expressing wild-type PSGL-1 or PSGL-1 constructs with substitutions in targeted N-terminal residues. Rolling through P- or L-selectin required a Thr or Ser at a specific position on PSGL-1, the attachment site for an essential O-glycan, but required only one of three nearby Tyr residues, which are sites for Tyr-SO3 formation. The adhesive strengths and numbers of cells rolling through P- or L-selectin were similar on wild-type PSGL-1 and on each of the three PSGL-1 constructs containing only a single Tyr. However, the cells rolled more irregularly on the single-Tyr forms of PSGL-1. Analysis of the lifetimes of transient tethers on limiting densities of PSGL-1 revealed that L-selectin dissociated faster from single-Tyr than wild-type PSGL-1 at all shears examined. In sharp contrast, P-selectin dissociated faster from single-Tyr than wild-type PSGL-1 at higher shear but not at lower shear. Thus, tyrosine replacements in PSGL-1 affect distinct kinetic and mechanical properties of bonds with P- and L-selectin.

Separation of the glucose-stimulated cytoplasmic and mitochondrial NAD(P)H responses in pancreatic islet β cells

Two-photon excitation microscopy was used to image and quantify NAD(P)H autofluorescence from intact pancreatic islets under glucose stimulation. At maximal glucose stimulation, the rise in whole-cell NAD(P)H levels was estimated to be ≈30 μM. However, because glucose-stimulated insulin secretion involves both glycolytic and Kreb's cycle metabolism, islets were cultured on extracellular matrix that promotes cell spreading and allows spatial resolution of the NAD(P)H signals from the cytoplasm and mitochondria. The metabolic responses in these two compartments are shown to be differentially stimulated by various nutrient applications. The glucose-stimulated increase of NAD(P)H fluorescence within the cytoplasmic domain is estimated to be ≈7 μM. Likewise, the NAD(P)H increase of the mitochondrial domain is ≈60 μM and is delayed with respect to the change in cytoplasmic NAD(P)H by ≈20 sec. The large mitochondrial change in glucose-stimulated NAD(P)H thus dominates the total signal but may depend on the smaller but more rapid cytoplasmic increase.

P-OTX: a PIT-1-interacting homeodomain factor expressed during anterior pituitary gland development.

A novel OTX-related homeodomain transcription factor has been identified on the basis of its ability to interact with the transactivation domain of the pituitary-specific POU domain protein, Pit-1. This factor, referred to as P-OTX (pituitary OTX-related factor), is expressed in primordial Rathke's pouch, oral epithelium, first bronchial arch, duodenum, and hindlimb. In the developing anterior pituitary, it is expressed in all regions from which cells with distinct phenotypes will emerge in the mature gland. P-OTX is able to independently activate and to synergize with Pit-1 on pituitary-specific target gene promoters. Therefore, P-OTX may subserve functions in generating both precursor and specific cell phenotypes in the anterior pituitary gland and in several other organs.