K Zin - Academia.edu (original) (raw)

Papers by K Zin

Transplantation, 2004

Background: Improvement of cardiac function by mechanical unloading (assist device) of the left v... more Background: Improvement of cardiac function by mechanical unloading (assist device) of the left ventricle are frequently to be observed. The composition of the different collagen in the extracellular matrix may be a main predictor for a possible improvement. Methods: We examined the Neutral Salt Soluble Collagen (NSC) and the Acid Soluble Collagen (ASC) content in the myocardium taken from three groups of patients. Group 1 (Nϭ18): healthy myocardium from non used donor hearts. Group 2 (Nϭ8) exists out of two subgroups, group 2a: myocardium of patients taken at the time of device implantation; group 2b: myocardium of the same patients taken at time of device removal (transplantation). Group 3 (Nϭ10): myocardium taken at time of device placement from patients who were later on weaned from device (no transplantation). Results: The mean amount of NSC of group 1 (3.61 g/mg) did not significantly differ from that of group 2a (3.16 g/mg), Pϭ0.507, however, after unloading it showed a significant increase in group 2b (4.69 g/mg), Pϭ0.2000. At the time of device placement, group 3 showed significant higher amount of NSC (5.63 g/mg) than in group 1 (Pϭ0.0001) and than in group 2a and 2b (Pϭ0.002; Pϭ0.028). As compared to group 1 (1.77 g/mg) the mean amount of ASC was significantly reduced in the group 2a (0.20 g/mg), Pϭ0.0001 and after unloading in group 2b (0.62 g/mg), Pϭ0.001. Group 1 and 3 (1.31 g/mg) did not statistically differ just as little group 2b (Pϭ0.114; Pϭ0.060). But group 2a showed a statistically lower ASC content than group 3, Pϭ0.002. Left heart ejection fraction before device placement was below 20% in all patients. At the time of device removal (transplantation) patients of group 2 were all below 35% and patients at device explantation (weaning) were all above 50%. Conclusions: By unloading NSC increases above the normal level of the control myocardium, ASC, however, remains significant below the normal control level. The increase in both collagen fractions could be regarded as an expression of the reverse of the maladaptive myocardial interstitial remodeling. The myocardium of patients with profound improvement of cardiac function so that weaning from the device had be performed revealed already at the time of device implantation a hyper-normal NSC and normal ASC. This can be interpreted as a predictor for later improvement. Myocardium with this collagen constellation seemed to had a favorable reaction to the disease process.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1990

Copper(II) pyruvaldehyde bis(N4-methylthiosemicarbazone) (Cu-PTSM), copper(II) pyruvaldehyde bis(... more Copper(II) pyruvaldehyde bis(N4-methylthiosemicarbazone) (Cu-PTSM), copper(II) pyruvaldehyde bis(N4-dimethylthiosemicarbazone) (Cu-PTSM2), and copper(II) ethylglyoxal bis(N4-methylthiosemicarbazone) (Cu-ETSM), have been proposed as PET tracers for cerebral blood flow (CBF) when labeled with generator-produced 62Cu (t1/2 = 9.7 min). To evaluate the potential of Cu-PTSM for CBF PET studies, baboon single-pass cerebral extraction measurements and PET imaging were carried out with the use of 67Cu (t1/2 = 2.6 days) and 64Cu (t1/2 = 12.7 hr), respectively. All three chelates were extracted into the brain with high efficiency. There was some clearance of all chelates in the 10-50-sec time frame and Cu-PTSM2 continued to clear. Cu-PTSM and Cu-ETSM have high residual brain activity. PET imaging of baboon brain was carried out with the use of [64Cu]-Cu-PTSM. For comparison with the 64Cu brain image, a CBF (15O-labeled water) image (40 sec) was first obtained. Qualitatively, the H2(15)O and [6...

Molecular pharmacology, 2006

Delivery of multiple exogenous genes into target cells is important for a broad range of gene the... more Delivery of multiple exogenous genes into target cells is important for a broad range of gene therapy applications, including combined therapeutic gene expression and noninvasive imaging. Previous studies ( Mol Ther 4: 223-231, 2001 ) have described the adenoviral vector RGDTKSSTR with a double-expression cassette that encodes herpes simplex virus thymidine kinase (HSVtk) for molecular chemotherapy and human somatostatin receptor subtype-2 (hSSTR2) for indirect imaging. In this vector, both genes are inserted in place of the E1 region of the adenoviral genome and expressed independently from two cytomegalovirus (CMV) promoters. During production of clinical-grade RGDTKSSTR, we found that the CMV promoters and simian virus 40 (SV40) poly(A) regions located in both expression cassettes provoked homologous recombination and deletion of one of the cassettes. To resolve this problem, we designed a strategy for substituting the duplicate promoters and poly(A) regions. We placed the hSSTR2...

The Journal of Neuroscience, 2010

We identified Pumilio (Pum), aDrosophilatranslational repressor, in a computational search for me... more We identified Pumilio (Pum), aDrosophilatranslational repressor, in a computational search for metazoan proteins whose activities might be regulated by assembly into ordered aggregates. The search algorithm was based on evolutionary sequence conservation patterns observed for yeast prion proteins, which contain aggregation-prone glutamine/asparagine (Q/N)-rich domains attached to functional domains of normal amino acid composition. We examined aggregation of Pum and its nematode ortholog PUF-9 by expression in yeast. A domain of Pum containing the Q/N-rich sequence, denoted as NQ1, the entire Pum N terminus, and the complete PUF-9 protein localize to macroscopic aggregates (foci) in yeast. NQ1 and PUF-9 can generate the yeastPin+ trait, which is transmitted by a heritable aggregate. NQ1 also assembles into amyloid fibrilsin vitro. InDrosophila, Pum regulates postsynaptic translation at neuromuscular junctions (NMJs). To assess whether NQ1 affects synaptic Pum activityin vivo, we exp...

Molecular Endocrinology, 2010

GH promotes longitudinal growth and regulates multiple cellular functions in humans and animals. ... more GH promotes longitudinal growth and regulates multiple cellular functions in humans and animals. GH signals by binding to GH receptor (GHR) to activate the tyrosine kinase, Janus kinase 2 (JAK2), and downstream pathways including signal transducer and activator of transcription 5 (STAT5), thereby regulating expression of genes including IGF-I. GH exerts effects both directly and via IGF-I, which signals by activating the IGF-I receptor (IGF-IR). IGF-IR is a cell surface receptor that contains intrinsic tyrosine kinase activity within its intracellular domain. In this study, we examined the potential role of IGF-IR in facilitating GH-induced signal transduction, using mouse primary calvarial osteoblasts with Lox-P sites flanking both IGF-IR alleles. These cells respond to both GH and IGF-I and in vitro infection with an adenovirus that drives expression of Cre recombinase (Ad-Cre) dramatically reduces IGF-IR abundance without affecting the abundance of GHR, JAK2, STAT5, or ERK. Notably, infection with Ad-Cre, but not a control adenovirus, markedly inhibited acute GH-induced STAT5 activity (more than doubling the ED 50 and reducing the maximum activity by nearly 50%), while sparing GH-induced ERK activity, and markedly inhibited GH-induced transactivation of a STAT5-dependent luciferase reporter. The effect of Ad-Cre on GH signaling was specific, as platelet-derived growth factor-induced signaling was unaffected by Ad-Cre-mediated reduction of IGF-IR. Ad-Cre-mediated inhibition of GH signaling was reversed by adenoviral reexpression of IGF-IR, but not by infection with an adenovirus that drives expression of a hemagglutination-tagged somatostatin receptor, which drives expression of the unrelated somatostatin receptor, and Ad-Cre infection of nonfloxed osteoblasts did not affect GH signaling. Notably, infection with an adenovirus encoding a C-terminally truncated IGF-IR that lacks the tyrosine kinase domain partially rescued both acute GH-induced STAT5 activity and GH-induced IGF-I gene expression in cells in which endogenous IGF-IR was reduced. These data, in concert with our earlier findings that GH induces a GHR-JAK2-IGF-IR complex, suggest a novel function for IGF-IR. In addition to its role as a key IGF-I signal transducer, this receptor may directly facilitate acute GH signaling. The implications of these findings are discussed.

Journal of Radioanalytical and Nuclear Chemistry Articles, 1995

The Journal of Membrane Biology, 1995

We used the short-lived radionuclide, S2Br-to follow 7-aminobutyrate (GABA) receptor-mediated hal... more We used the short-lived radionuclide, S2Br-to follow 7-aminobutyrate (GABA) receptor-mediated halide exchange into membrane vesicles from rat cerebral cortex in millisecond and second time regions using quench-flow technique. The radioisotope was prepared by neutron capture [81Br-(n,y)S2Br-] on irradiation of a natural isotope of bromine, 8tBr-in a neutron flux. 82Brdecays by p-emission with secondary y-emission. Possible advantages of 82Brover 36C1-in anion tracer measurements include, (a) a short lifetime (h/2 = 35.3 hr), which alleviates contamination and disposal problems, (b) high counting efficiency (1.54) due to the secondary radiation, (c) measurement with a 7-counter as well as a [~-counter, (d) a simple preparation not requiring subsequent purification steps giving a specific activity depending on the irradiation time. With 6 hr irradiation time the specific activity was sufficient to make measurements with <1 mM Br-, which is less than the bromide concentration known to affect the properties of GABA a receptor. The radiotracers, 82Br-and 36C1-could be compared with the same solution composition. In conditions where a direct effect of binding of halide to receptor does not contribute to a difference in measured ion-flux, S2Brwas translocated only marginally faster than 36C1-. The effect of chlordiazepoxide (CDPX) (2-250 gM) on the progress of GABA (10 gM)-mediated 82Br-uptake was measured in a time range of 200 msec to 20 sec using quench-flow technique. The two phases of anion exchange previously reported in this experimental model with GABA alone were observed. The rate of 82Br-exchange was increased 2.3-fold at 30-60 ptM CDPX and was not further increased with increasing [CDPX]. The rate of halide exchange is a measure of open channel concentration. The isotope exchange rate constant, J, in Correspondence to: D.J. Cash a membrane vesicle preparation, is a measure of the membrane permeability per internal volume/surface area, J = PmA/V. Receptor desensitization rate was also increased by CDPX, but unlike the isotope exchange rate, it continued to increase up to at least 250 gM CDPX.

Infection, 1976

Humorale und zellul&re immunphfinomene im klinischen Verlauf der chronischen posttraumatischen Os... more Humorale und zellul&re immunphfinomene im klinischen Verlauf der chronischen posttraumatischen Osteomyelitis Zusammenfassung: Neunzig Patienten mit chronischer posttraumatischer Osteomyelitis wurden immunologisch untersncht. Die Ergebnisse wurden mit einer Kontrollgruppe yon 35 gesunden Freiwilligen verglichen. In 10-20% der Patienten fanden sich erh6hte Serum-IgG-und IgM-Konzentrationen; in 5-10% waren diese erniedrigt. Unter 55 Patienten mit Staphylokokkeninfektion zeigten nur 25 einen positiven Antistaphylolysintiter. Elf yon 25 untersuchten Patienten mit Staphylokokken-Osteomyelitis zeigten eine positive in-vitro-Lymphozytentransformation nach Stimulation mit a-Staphylolysin (durchschnittliche Transformationsrate 5,4 +_ 0,9). Dabei war die Phytohiimagglutinin-sowie die Pokeweed-Mitogen-Antwort normal. Ein Vergleich der immunologischen Reaktionslage der Patienten mit dem Schweregrad der klinischen Erkrankung ergab, dab die schwersten Verl~iufe in der Gruppe der Patienten mit nachweisbarer zellul~irer Oberempfindlichkeit gefunden wurden.

Gene Therapy, 2004

In clinical trials with cancer patients, the safety of conditionally replicating adenoviruses (CR... more In clinical trials with cancer patients, the safety of conditionally replicating adenoviruses (CRAds) has been good. However, marginal data are available on the persistence or antitumor efficacy of these agents. The oncolytic potency of CRAds is determined by their capacity for entering target cells. Consequently, we constructed a retargeted CRAd featuring a secreted marker protein, soluble human carcinoembryogenic antigen (hCEA), which can be measured in growth medium or plasma. We found that virus replication closely correlated with hCEA secretion both in vitro and in vivo. Further, antitumor efficacy and the persistence of the virus could be deduced from plasma hCEA levels. Finally, using in vivo bioluminescence imaging, we were able to detect effective tumor cell killing by the virus, which led to enhanced therapeutic efficacy.

Cell, 1985

We have localized the regulatory sequence required for viral or poly(I)-poly(C) activation of hum... more We have localized the regulatory sequence required for viral or poly(I)-poly(C) activation of human/3-interferon gene expression to a region located between-37 and-77 from the mRNA cap site. This sequence has the characteristics of an inducible enhancer element: it can act upstream or downstream of the p-interferon gene regardless of its orientation, and at distances up to approximately 1 kilobase from its normal location. Moreover, this element can confer inducibility on a heterologous promoter. Further analysis has identified a minimal regulatory element of 14 base pairs within this enhancer. Sequences closely related to this element are present five times within the 5'flanking regions of both the a-and f3-interferon genes. The number of these minimal regulatory elements required for maximal p-interferon gene expression appears to differ in different cell lines.

Cell, 1983

To study the regulation of the human beta-interferon (beta-IFN) gene by poly(I)-poly(C), we analy... more To study the regulation of the human beta-interferon (beta-IFN) gene by poly(I)-poly(C), we analyzed the expression of deletion mutants of the cloned gene introduced into mouse cells on a new bovine papilloma virus (BPV) vector. In stable cell lines transformed by a BPV-IFN plasmid containing the beta-IFN structural gene with 210 bp of DNA to the 5' side of its mRNA cap site (denoted -210), human beta-IFN mRNA is induced approximately 400-fold by poly(I)-poly(C), and reproducible levels of expression are observed for independent cell lines. Our studies indicate that there are two distinct regulatory regions adjacent to the gene, located between -77 and -19, and between -210 and -107. The -77 to -19 region is required for constitutive and induced IFN gene expression, and both are drastically reduced by deletion to -73. When sequences between -210 and -107 are deleted, the constitutive level of IFN gene expression is increased 5- to 10-fold, while induced expression is essentially unaffected. Deletion of the -210 to -107 region also alters the kinetics of induction of the gene.

Cell, 1988

The fasciclin I, II, and III glycoproteins are expressed on different subsets of axon bundles (fa... more The fasciclin I, II, and III glycoproteins are expressed on different subsets of axon bundles (fascicles) in insect embryos and are thus candidates for surface recognition molecules involved in growth cone guidance. Here we present the sequence of grasshopper fasciclin I and the identification and sequence of the Drosophila fasciclin I homolog. In both species, fasciclin I appears to be an extrinsic membrane protein with a signal sequence but no transmembrane region; the protein comprises four homologous domains of approximately 150 amino acids each. Antibodies against Drosophila fasciclin I reveal that it is expressed on the surface of a subset of commissural axon pathways in the embryonic central nervous system and on all sensory axon pathways in the peripheral nervous system. This pattern of expression is similar to that in grasshopper.