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PubMed2002

The association of incident dementia with mortality in PD.

OBJECTIVE: To evaluate the association of incident dementia with mortality in a cohort of patients with idiopathic PD who were nondemented at baseline evaluation, controlling for extrapyramidal sign (EPS) severity at each study visit. BACKGROUND: The development of dementia has been associated with reduced survival in PD. Because EPS severity is associated with both dementia and mortality in PD, the association of dementia with mortality may be confounded by disease severity. METHODS: A cohort of patients with PD was followed annually with neurologic and neuropsychological evaluations. The association of incident dementia and the total Unified PD Rating Scale (UPDRS) motor score with mortality in PD was examined using Cox proportional hazards models with time-dependent covariates. All analyses were adjusted for age at baseline, sex, years of education, ethnicity, and duration of PD. RESULTS: Of 180 PD patients, 41 (22.8%) died during a mean follow-up period of 3.9 +/- 2.2 years. Among those who died during the study period, 48.8% (20 of 41) became demented during follow-up, as compared to 23.0% (32 of 139) of those who remained alive. Both incident dementia (RR: 2.2, 95% CI: 1.1 to 4.5, p = 0.04) and the total UPDRS motor score at each study visit (RR: 1.04, 95% CI: 1.02 to 1.07, p = 0.001) were associated with mortality in PD when included in the same Cox model. CONCLUSIONS: Incident dementia has an independent effect on mortality when controlling for EPS severity. The development of dementia is associated with a twofold increased mortality risk in PD.

Aged↗
PubMed2003

Strong association between N-acetyltransferase 2 genotype and PD in Hong Kong Chinese.

BACKGROUND: The slow acetylator genotype for N-acetyltransferase 2 (NAT2 genotype) may be associated with PD in white subjects and the genotype is common in both white and Chinese populations. Whether there is a relationship between NAT2 genotype and PD in Chinese subjects is not known. OBJECTIVE: To investigate the association between the slow acetylator genotype for N-acetyltransferase 2 and PD in a Chinese population. METHODS: The authors obtained DNA samples and documented sex, age, and smoking history in 99 Chinese patients with PD and in 126 control subjects from two major Hong Kong hospitals. PCR-restriction fragment length polymorphism was used to identify M1, M2, and M3 mutant polymorphisms of the slow acetylator genotype for N-acetyltransferase 2. Logistic regression analyses were carried out to investigate the relationships between the different variables and PD. RESULTS: The frequency of the slow acetylator genotype for N-acetyltransferase 2 in the PD group was significantly higher than that of the control group (68.7% vs 28.6%) with an OR of 5.53 (95% CI 3.08 to 9.92) after adjusting for age, sex, and smoking history. In a subgroup analysis smoking had no modifying effect on the association between genotype and PD. CONCLUSIONS: There is a significant association between PD and the slow acetylator genotype for N-acetyltransferase 2 in Hong Kong Chinese. The OR found is among the highest reported so far in all susceptibility gene studies for PD in both Chinese and white subjects and provides evidence for a possible functional relationship between NAT2 slow acetylator genotype and PD in both racial groups.

Acetylation↗
PubMed1999

Abnormal performance on the PD test battery by asymptomatic first-degree relatives.

OBJECTIVE: To determine whether a sensitive and specific battery of tests (PD Battery) could identify a subset of asymptomatic first-degree relatives (FDRs) of PD patients who were significantly more impaired than age-matched normal control (NC) subjects. The PD Battery incorporates tests of motor function, olfaction, and mood. In previous studies, it has shown high specificity and sensitivity in distinguishing mildly affected PD patients from NC subjects. METHODS: The PD Battery and regression analysis-derived scoring equations were applied to asymptomatic FDRs. RESULTS: Eighty FDRs and 100 NC subjects were tested. Of the FDRs, 22.5% scored in the abnormal range, and 9% of NC subjects had abnormal scores. This difference was statistically significant. Further analysis demonstrated that FDRs with abnormal scores on the PD Battery differed on all three components of the test battery from FDRs who had normal scores. Among the sons and daughters whose scores were abnormal, there was a much higher prevalence of the affected parent being the father. CONCLUSIONS: The proportion of FDRs who demonstrated abnormal performance on the PD Battery was greater than that of NC subjects. Thus, the PD Battery may detect the asymptomatic carrier state or risk for PD. Sons and daughters whose scores were in the abnormal range were more likely to have fathers with PD.

Adult↗
PubMed2006

Cutting Edge: Programmed death (PD) ligand-1/PD-1 interaction is required for CD8+ T cell tolerance to tissue antigens.

Constitutive presentation of tissue Ags by dendritic cells results in tolerance of autoreactive CD8+ T cells; however, the underlying molecular mechanisms are not well understood. In this study we show that programmed death (PD)-1, an inhibitory receptor of the CD28 family, is required for tolerance induction of autoreactive CD8+ T cells. An antagonistic Ab against PD-1 provoked destructive autoimmune diabetes in RIP-mOVA mice expressing chicken OVA in the pancreatic islet cells, which received naive OVA-specific CD8+ OT-I cells. This effect was mediated by the PD ligand (PD-L) PD-L1 but not by PD-L2. An increased number of effector OT-I cells recovered from the pancreatic lymph nodes of anti-PD-L1-treated mice showed down-regulation of PD-1. Furthermore, the blockade of PD-1/PD-L1 interaction during the priming phase did not significantly affect OT-I cell division but enhanced its granzyme B, IFN-gamma, and IL-2 production. Thus, during the presentation of tissue Ags to CD8+ T cells, PD-1/PD-L1 interaction crucially controls the effector differentiation of autoreactive T cells to maintain self-tolerance.

Animals↗
PubMedDate not supplied

Glucose-6-phosphate dehydrogenase (G-6-PD) levels in jaundiced neonates in Calabar.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G-6-PD) is an enzyme in the first step of the hexose-monophosphate shunt required for the generation of nicotinamide adenine dinucleotide phosphate (NADPH). Red blood cells of neonates with deficient G-6-PD are potentially susceptible to acute severe haemolysis and may result in haemolytic jaundice. This study was to determine the association between neonatal jaundice and G-6-PD activity and the degree of deficiency of this enzyme among the affected neonates. METHODS: G-6-PD levels in jaundiced neonates admitted into the Special Care Baby Unit (SCBU) of the University of Calabar Teaching Hospital were assayed between May 2000 and April 2001 using Biotic (London) diagnostic assay kit method. Data was analyzed using SPSS (base 705) data Editor (Microsoft Windows 95). RESULTS: A total of 102 jaundiced neonates between ages 1 and 10 days were studied. Out of the 102 jaundiced neonates, 39 (38.2%) were G-6-PD deficient with G-6-PD concentration of 48.89 +/- 72 mU/10(12) erythrocyte compared to 129.51 +/- 0.92 mU/10(12) erythrocyte in the remaining 63 subjects. The prevalence rate of G-6-PD deficiency among jaundiced neonates was 38% which is significantly high (p < 0.05) considering the study sample size. There was no significant difference (p > 0.05) in G-6-PD level in the males and females. CONCLUSION: G-6-PD activity is low in a number of jaundiced patients. Routine assay of G-6-PD in jaundiced patients is recommended.

Glucosephosphate Dehydrogenase↗
PubMed1980

[Studies on Pd base ternary alloys for dental amalgam. (Part 2) On the corrosion resistivity (author's transl)].

In the previous paper, the author reported the effect of composition of Pd base ternary alloys on the dimensional change, the compressive strength, hardness and microanalysis by EPMA. In this paper, corrosion resistivity of Pd base ternary alloy amalgam was studied by comparison of reflective light intensity, surface roughness and weight change before and after corosion test in 0.1% Na2S, 0.1% lactive acid and 1% NaCl solution. The main results obtained are as follows: (1) Pd base ternary alloy amalgam showed much higher corrosion resistivity than that of on the market silver-tin-copper amalgam. (2) On the (60 Pd-40 Ag)-Sn alloy amalgam, corrosion resistivity was gradually improved by addition of Sn up to 10 wt% Sn, and the best corrosion resistivity was observed in (60 Pd-40 Ag)-10 Sn among Pd base alloy amalgam tested in this study. (3) On the (60 Pd-40 Ag)-Cu alloy amalgam, corrosion resistivity decreased gradually with increment of Cu content. (4) Weight of (60 Pd-40 Ag)-Sn alloy amalgam was a little increased after corrosion test in 0.1% Na2S solution, but that of (60 Pd-40 Ag)-Cu alloy amalgam showed a tendancy to decrease. (5) Corrosion of Pd base alloy amalgam was observed mainly in the matrix. Tarnish on the core was observed a little. Since fine cut amalgam has the smaller rate of area of core than that of spherical amalgam, surface roughness was comparatively large.

Copper↗
PubMed1995

Neurochemical and functional characterization of the preferentially selective dopamine D3 agonist PD 128907.

The present study determined the biochemical and pharmacological effects of PD 128907 [R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H- [1]benzopyrano[4,3-b]-1,4-oxazin-9-ol], a dopamine (DA) receptor agonist that shows a preference for the human D3 receptor. In transfected Chinese hamster ovary cells (CHO K1), PD 128907 displaced [3H]spiperone in a biphasic fashion which fit best to a two-site model, generating Ki values of 20 and 6964 nM for the high- and low-affinity sites for the D2L receptors and 1.43 and 413 nM for the corresponding sites for the D3 receptors. Addition of sodium and the GTP analog Gpp(NH)p to both the D2L and D3 caused a modest reduction in the affinity of the compound suggestive of an agonist type action. In agonist binding ([3H]N-0437), PD 128907 exhibited an 18-fold selectivity for D3 versus D2L, a selectivity similar to that found with antagonist binding to the high-affinity sites. PD 128907 exhibited only weak affinity for D4.2 receptors (Ki = 169 nM). No significant affinity for a variety of other receptors was observed. PD 128907 stimulated cell division (measured by [3H]thymidine uptake) in CHO p-5 cells transfected with either D2L or D3 receptors exhibiting about a 6.3-fold greater potency in activating D3 as compared to D2L receptors. In vivo the compound was active in reducing DA synthesis both in normal and gamma-butyrolactone (GBL) treated rats; in the GBL model, the decrease was greater in the higher D3-expressing mesolimbic region as compared with striatum which has a lower expression of D3 receptors. PD 128907 decreased DA release (as measured by brain microdialysis) both in rat striatum, nucleus accumbens and medial frontal cortex, as well as in monkey putamen. Behaviorally PD 128907 decreased spontaneous locomotor activity (LMA) in rats at low doses, whereas at higher doses stimulatory effects were observed. PD 128907 at high doses reversed the reserpine-induced decrease in LMA and induced stereotypy in combination with the D1 agonist SKF 38393 indicating postsynaptic DA agonist actions. It is unclear which of the subtypes of DA receptors might be mediating the pharmacological effects of PD 128907. However, the present findings indicating that PD 128907 shows a preference for DA D3 over D2L and D4.2 receptors indicates that its action at low doses may be due to interaction with D3 receptors and at higher doses, with both D2 and D3 receptors.

Animals↗
PubMed1996

Multiple use of disposable (tubing) set of HomeChoice automated peritoneal dialysis (APD) system in PD patients.

Our objective was to evaluate the multiple use of the tubing set of the HomeChoice automated peritoneal dialysis (PD) system in PD patients. The study was designed to reuse the tubing set of the HomeChoice automated PD system for two to seven treatments, each of 16-24 hours duration, in end-stage renal disease (ESRD) patients, and to continue to use the same set if the patient was disconnected for any reason. In a tertiary-referral university hospital, 17 ESRD patients on PD, admitted to a university hospital from January, 1995 to September, 1995, were studied. The patients were disconnected and connected in between or during PD treatments. Five-liter bags were used. All the fluid was either set initially or added as clinically indicated. One hundred and thirty-eight PD treatments were performed with the HomeChoice automated PD system, using 30 disposable (tubing) sets. Sixty-three disconnections were made for ambulation, transfer to other units, surgery, physical therapy, radiological investigations, and special procedures in between and during PD treatments. No episode of peritonitis occurred. The multiple use resulted in a 78% reduction in tubing sets and drain-line extension sets used, thereby reducing the disposable supplies and creating a substantial saving in nursing time. The multiple use of tubing sets of the HomeChoice automated PD system was safe and economical in patients undergoing automated PD in a hospital setting.

Catheters, Indwelling↗
PubMed1997

In vitro pharmacological characterization of PD 166285, a new nanomolar potent and broadly active protein tyrosine kinase inhibitor.

PD 166285, a novel protein tyrosine kinase inhibitor of a new structural class, the 6-aryl-pyrido[2,3-d]pyrimidines, was synthesized as the most potent and soluble analog of a series of small molecules originally identified by screening a compound library with assays that measured protein tyrosine kinase activity. PD 166285 was found to inhibit Src nonreceptor tyrosine kinase, fibroblast growth factor receptor-1, epidermal growth factor receptor and platelet-derived growth factor receptor beta subunit (PDGFR-beta), tyrosine kinases with half-maximal inhibitory potencies (IC50 values) of 8.4 +/- 2.3 nM (n = 6), 39.3 +/- 2.8 nM (n = 16), 87.5 +/- 13.7 nM (n = 6) and 98.3 +/- 7.9 nM (n = 16), respectively. PD 166285 also demonstrated inhibitory activity against mitogen-activated protein kinase (IC50 = 5 microM) and protein kinase C (IC50 = 22.7 microM). PD 166285 was further characterized as an ATP competitive inhibitor of Src nonreceptor tyrosine kinase, PDGFR-beta, fibroblast growth factor receptor-1 and epidermal growth factor receptor tyrosine kinases. In addition, PD 166285 inhibited PDGF- and EGF-stimulated receptor autophosphorylation in vascular smooth muscle cells (VSMCs) and A431 cells, respectively, and basic fibroblast growth factor-mediated tyrosine phosphorylation in Sf9 cells, with IC50 values of 6.5 nM, 1.6 microM and 97.3 nM, respectively, further establishing a tyrosine kinase mechanism of inhibition. The inhibition of PDGF receptor autophosphorylation in VSMCs by PD 166285 was long lasting and persisted for 4 days after a single 1-hr exposure followed by extensive washing. The PDGF-induced tyrosine phosphorylation of the 44- and 42-kDa mitogen-activated protein kinase isoforms was also blocked as a result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD 166285 in VSMCs. The effects of PD 166285 were also demonstrated in functional assays of cell attachment, migration and proliferation, in which vascular cell adhesion to vitronectin, PDGF-directed chemotaxis and serum-stimulated cell growth were all potently inhibited with IC50 values of 80 yo 120 nM. Finally, PD 166285 uniquely demonstrated potent inhibition of phorbol ester-induced production of 92-kDa gelatinase A (MMP-9) in VSMC without affecting 72-kDa gelatinase B (MMP-2) as measured by gelatin zymography. These results highlight the biological characteristics of PD 166285 as a broadly active protein tyrosine kinase capable of potently inhibiting a number of kinase mediated cellular functions, including cell attachment, movement and replication. The potential therapeutic utility of this broadly acting inhibitor as an antiproliferative and antimigratory agent could extend to such diseases as cancer, atherosclerosis and restenosis, in which redundancies in protein kinase signaling pathways are known to exist.

Animals↗
PubMed1998

In vitro biological characterization and antiangiogenic effects of PD 166866, a selective inhibitor of the FGF-1 receptor tyrosine kinase.

Through direct synthetic efforts, we discovered a small molecule that is a nanomolar inhibitor of the human fibroblast growth factor-1 receptor (FGFR) tyrosine kinase. PD 166866, a member of a new structural class of tyrosine kinase inhibitors, the 6-aryl-pyrido[2,3-d]pyrimidines, was identified by screening a compound library with assays that measure protein tyrosine kinase activity. PD 166866 inhibited human full-length FGFR-1 tyrosine kinase with an IC50 value of 52.4 +/- 0.1 nM and was further characterized as an ATP competitive inhibitor of the FGFR-1. In contrast, PD 166866 had no effect on c-Src, platelet-derived growth factor receptor-beta, epidermal growth factor receptor or insulin receptor tyrosine kinases or on mitogen-activated protein kinase, protein kinase C and CDK4 at concentrations as high as 50 microM. PD 166866 was a potent inhibitor of basic fibroblast growth factor (bFGF)-mediated receptor autophosphorylation in NIH 3T3 cells expressing endogenous FGFR-1 and in L6 cells overexpressing the human FGFR-1 tyrosine kinase, confirming a tyrosine kinase-mediated mechanism. PD 166866 also inhibited bFGF-induced tyrosine phosphorylation of the 44- and 42-kDa (ERK 1/2) mitogen-activated protein kinase isoforms in L6 cells, presumably via inhibition of bFGF-stimulated FGFR-1 tyrosine kinase activation. PD 166866 did not inhibit platelet-derived growth factor, epidermal growth factor or insulin-stimulated receptor autophosphorylation in vascular smooth muscle, A431 or NIHIR cells, respectively, further supporting its specificity for the FGFR-1. In addition, daily exposure of PD 166866 to L6 cells at concentrations from 1 to 100 nM resulted in a concentration-related inhibition of bFGF-stimulated cell growth for 8 consecutive days with an IC50 value of 24 nM. In contrast, PD 166866 had little effect on platelet-derived growth factor-BB-stimulated growth of L6 cells or serum-stimulated vascular smooth muscle cell proliferation. Finally, PD 166866 was found to be a potent inhibitor of microvessel outgrowth (angiogenesis) from cultured artery fragments of human placenta. These results highlight the discovery of PD 166866, a new nanomolar potent and selective small molecule inhibitor of the FGFR-1 tyrosine kinase with potential use as antiproliferative/antiangiogenic agent for such therapeutic targets as tumor growth and neovascularization of atherosclerotic plaques.

3T3 Cells↗
PubMedDate not supplied

The use of the PD Adequest mathematical model in pediatric patients on chronic peritoneal dialysis.

OBJECTIVE: To test the accuracy of the PD ADEQUEST kinetic model in calculating peritoneal transport parameters and to quantify the differences between the results of software simulations and direct measurements in order to assess the reliability of this tool in chronic peritoneal dialysis (PD) pediatric patients. PATIENTS: Twenty-nine patients (mean age: 10 +/- 4 years; range: 4-17), 5 on continuous ambulatory PD, 4 on continuous cycling PD, 19 on nocturnal intermittent PD and 1 in nocturnal tidal PD, all free from peritonitis in the previous 2 months. Fourteen patients were anuric and 15 had a mean glomerular filtration rate of 1.79 +/- 1.23 mL/min, range 0.25-4.82. METHODS: In all patients, 24-hour dialysate and urine collections associated to standard peritoneal equilibration test (PET) were performed using their usual dialytic regimen and fill volume (1023 +/- 159 mL/m2 BSA, range 614-1361). PD ADEQUEST kinetic parameters were compared with pediatric and adult data from literature. The measured weekly normalized total creatinine clearance (CRCL), weekly total Kt/V, and daily net ultrafiltration (UF) were compared with corresponding mathematically modeled values. RESULTS: Kinetic parameters calculated by the PD ADEQUEST program were comparable to adult and pediatric values from previous studies after normalization for BSA. Measured and modeled CRCL and Kt/V showed a good agreement [concordance correlation (rc) 0.937 and 0.768, respectively] with limited median percentage absolute errors (11.6% and 10.2%, respectively). Ultrafiltration showed less favorable results (rc = 0.600 and median percentage absolute error 45%) probably owing to the wide variability of this parameter. When the analysis was restricted to the peritoneal component, the rc coefficients results were 0.745 for CRCL and 0.512 for Kt/V (median absolute error: 11.6% and 15.2%, respectively). CONCLUSIONS: The overall findings of our study show that the PD ADEQUEST kinetic model can be used in pediatric patients for the calculation of kinetic indexes and for mathematical simulation of the various regimens. We also feel that the results yielded by the PD ADEQUEST program are reliable enough for this computerized mathematical model to be used in the prescription management of pediatric patients. Only UF prediction needs to be used with a certain caution on account of the marked variability of this parameter.

Adult↗
PubMed1999

Adenosine A1 receptor-dependent and -independent effects of the allosteric enhancer PD 81,723.

The 2-amino-3-benzoylthiophene PD 81,723 has been shown to exhibit allosteric enhancement of adenosine A1 receptor binding and function. The aim of this study was to clarify the mechanism of this effect using membranes purified from rat brain and Chinese hamster ovary (CHO)-A1 cells that stably express the rat adenosine A1 receptor as well as intact CHO-A1 and nontransfected CHO cells. In membranes containing 100 microM magnesium, (2-amino-4, 5-dimethyl-3-thienyl)-[3-(trifluoromethyl)phenyl]methanone (PD 81, 723) significantly increased the affinity of the adenosine A1 receptor agonist, cyclopentyladenosine, for the low-affinity receptor without affecting high-affinity binding or Bmax. In intact cells, PD 81,723 inhibited basal adenylyl cyclase (AC) activity as well as forskolin-, cholera toxin-, and pertussis toxin-stimulated AC activity in CHO-A1 and CHO cells. Basal AC activity was inhibited 49% in CHO and 82% in CHO-A1 cells by 30 microM PD 81,723. In CHO-A1 cells, half-maximal inhibition of forskolin-stimulated AC occurred at 5 microM PD 81,723 compared to 10 microM in CHO cells. Cholera toxin-stimulated AC was reduced 90% in both CHO and CHO-A1 cells by 30 microM PD 81,723. At the same concentration of PD 81,723, pertussis toxin-stimulated AC activity was reduced 86% (CHO-A1) and 77% (CHO). [3H]forskolin was displaced from purified rat liver AC by PD 81,723 with an IC50 of 96 microM. These results demonstrate that two mechanisms appear to contribute to the observed effects of PD 81, 723. One mechanism is allosteric enhancement of adenosine A1 receptor function. Results from transfected and nontransfected cells suggest that PD 81,723 also inhibits AC directly by binding to the catalytic unit at or near the forskolin-binding site.

Adenylate Cyclase Toxin↗
PubMed2026

Dual-dimensional profiling of host genomic variations and HPV integration in PD-L1-stratified cervical cancer via Oxford Nanopore Technology.

BACKGROUND: The integration of human papillomavirus (HPV) DNA into the host genome is a key step in the development of HPV-associated cervical cancer (CC). However, the genomic characteristics of host genomic variations and HPV integration within the context of programmed death-ligand 1 (PD-L1) expression stratification have not been systematically investigated. METHODS: Whole-genome sequencing was performed using Oxford Nanopore Technology (ONT) on six samples (three from the high PD-L1 expression group and three from the low PD-L1 expression group). The characteristics of host genomic variations under different PD-L1 expression stratifications were explored, including structural variations (SV), copy number variations (CNV), single nucleotide polymorphisms (SNP), and insertion-deletions (Indel). Subsequently, the distribution features of HPV integration sites were analyzed, different integration types were identified, and pathway analysis was conducted. RESULTS: Whole-genome SV analysis revealed that the total number of SVs and the composition of mutation types were similar between the high and low PD-L1 expression groups, with insertions (INS) and deletions (DEL) predominating in both. These variations were primarily enriched in intergenic regions and introns. In the low PD-L1 expression group, integration events were observed at multiple chromosomal loci, with the most frequent integration occurring in the KLF5 gene region on chromosome 13. No frequently integrated loci were identified in the high PD-L1 expression group. Additionally, four distinct HPV integration breakpoint patterns were preliminarily identified and analyzed. CONCLUSION: PD-L1 expression stratification did not significantly alter the overall genomic instability of the host. However, differences were observed in the distribution patterns of HPV integration sites. These findings provide new insights into the genomic heterogeneity of CC under different PD-L1 expression backgrounds and may lay the groundwork for future research exploring stratified immunotherapy based on HPV integration features.

Humans↗
PubMed2002

Highly active palladium/activated carbon catalysts for Heck reactions: correlation of activity, catalyst properties, and Pd leaching.

A variety of palladium on activated carbon catalysts differing in Pd dispersion, Pd distribution, Pd oxidation state, and water content were tested in Heck reactions of aryl bromides with olefins. The optimization of the catalyst (structure-activity relationship) and reaction conditions (temperature, solvent, base, and Pd loading) allowed Pd/C catalysts with very high activity for Heck reactions of unactivated bromobenzene (turnover number (TON) approximately 18000, turnover frequency (TOF) up to 9000, Pd concentrations down to 0.005 mol %) to be developed. High Pd dispersion, low degree of reduction, sufficient content of water, and uniform Pd impregnation are criteria for the most active system. The catalysts combine high activity and selectivity under ambient conditions (air and moisture), easy separation (filtration), and quantitative recovery of palladium. Determination of Pd in solution after and during the reaction, and catalyst characterization before and after the reaction (transmission electron microscopy (TEM), X-ray diffraction (XRD)), indicate dissolution/reprecipitation of palladium during the reaction. The Pd concentration in solution is highest at the beginning of the reaction and is a minimum (< 1 ppm) at the end of the reaction. Palladium leaching correlates significantly with the reaction parameters.

Journal Article↗
PubMed2006

Control of optically active structure of thioether-phthalocyanine aggregates by chiral Pd(II)-BINAP complexes in toluene and at the toluene/water interface.

The Pd(II)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP)-mediated chiral assembly of thioether-derivatised phthalocyanatomagnesium(II) compounds (MgPc(SR)8, SR is benzylthio (SBz) or benzhydrylthio (Bh)) was formed in toluene and at the toluene/water interface, and investigated by means of UV-Vis absorption and circular dichroism (CD) spectroscopy combined with the centrifugal liquid-membrane (CLM) devise. Interfacial tension measurements indicated that, in the presence of PdSO4 in the aqueous phase, BINAP ligand adsorbed as a monolayer forming Pd(II)BINAP2+ complex at the toluene/water interface. UV-Vis absorption spectrum of MgPc(SR)8 in the Q-band region was blue-shifted in toluene upon addition of [Pd(II)BINAP]Cl2, but red-shifted at the toluene/water interface when Pd(II)BINAP2+ was formed at the interface. These results suggested that MgPc(SR)8-Pd(II)BINAP complex formed H-aggregate (face-to-face type) in toluene solution and J-aggregate (end-to-end type) at the toluene/water interface, respectively. Moreover, the specific bisignate CD spectral pattern in both systems indicated that the aggregates of MgPc(SR)8-Pd(II)BINAP complexes were chirally twisted, well controlled by the chirality of BINAP ligand. Very interestingly, the morphology of MgPc(SBz)8-Pd(II)BINAP and MgPc(SBh)8-Pd(II)BINAP aggregates formed at the toluene/water interface were significantly different as the rodlike and the ribbonlike crystalline structure, respectively, as observed by a scanning electron microscopy (SEM). On the basis of these experimental results, we proposed schematic molecular models of the chiral aggregates of MgPc(SR)8-Pd(II)BINAP complexes and demonstrated the specific role of the toluene/water interface.

Circular Dichroism↗
PubMed2006

Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro.

Human tumors frequently escape immune destruction, despite the presence of cytotoxic T cells (CTL) recognizing tumor-associated antigens (TAA). We have previously shown that programmed death ligand-1 (PD-L1), a recently identified ligand of the B7 superfamily, is expressed on murine tumors and can inhibit antitumor immune responses. To evaluate the clinical relevance of our animal model findings, we examined human tumors and tumor-specific T cells. We found PD-L1 to be constitutively expressed on human renal cell carcinoma (RCC) cell lines and upregulated on human melanoma cell lines upon exposure to interferon-gamma. Similarly, we found binding of anti-PD-L1 monoclonal antibody (mAb) on frozen sections from RCC and melanomas, but not on normal tissues. The corresponding inhibitory receptor of PD-L1, PD-1, revealed a higher expression on tumor-infiltrating lymphocytes than on peripheral blood lymphocytes (PBL) from melanoma patients upon specific antigen stimulation. Stimulation of PBL from healthy donors with peptide-loaded dendritic cells in the presence of anti-PD-L1 mAb altered neither the total T cell numbers after expansion, nor the percentage of peptide-specific CTL, when providing a T cell help by addition of cytokines. However, when stimulating TAA-specific CTL and T helper cells with Ag-pulsed dendritic cells in the absence of exogenous cytokines, PD-L1 blockade increased the cytokine production. Similar to the data achieved in the murine system, the blockade of PD-L1 on human tumors resulted in enhanced cytolytic activity of TAA-specific CTLs and cytokine production of TAA-specific T helper cells when interacting directly with the tumor. In summary, our data suggest that PD-L1/PD-1 interactions negatively regulate T cell effector functions predominantly in the absence of exogenous cytokine support, indicating an important role for this pathway in tumor evasion.

Antibodies, Monoclonal↗
PubMed1987

PD 115,199: an antagonist ligand for adenosine A2 receptors.

PD 115,199, N-[2-(dimethylamino)ethyl]-N-methyl-4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3- dipropyl-1H-purin-8-yl)benzenesulfonamide, was found to have high affinity for the A2 adenosine receptor labeled by 3H-NECA in rat striatal membranes (Ki 15.5 nM). Unlike other potent adenosine antagonists, which always showed some degree of selectivity for the A1 receptor, PD 115,199 had equal affinity at A1 and A2 receptors (Ki in 3H-CHA binding to A1 receptors 13.9 nM). 3H-PD 115,199 (126 Ci/mmol) was prepared by reduction of the diallyl analog, and binding experiments were performed with 0.5 nM 3H-PD 115,199 at 25 degrees C in rat striatal membranes. By nonlinear least-squares analysis of the concentration-inhibition curve for the highly A1-selective adenosine antagonist PD 116,948 (8-cyclopentyl-1,3-dipropylxanthine), it could be demonstrated that about 11% of specific 3H-PD 115,199 binding was to A1 receptors, and the remainder to A2 receptors. A 20 nM concentration of PD 116,948 was included in subsequent experiments to eliminate the A1 component of binding. The remaining binding had a Kd of 2.6 nM and Bmax of 56 pmol/g wet weight. Specific binding was about 79% of total binding. Affinities of compounds in the 3H-PD 115,199 assay were consistent with binding to a high-affinity A2 receptor: antagonists were consistently about three times more potent in 3H-PD 115,199 binding than in 3H-NECA binding, whereas agonists were consistently about fivefold less potent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion.

Recent clinical data support ideas of Programmed death receptor-ligand 1 (PD-L1; also called B7-H1, CD274) playing an important role in immune evasion of tumor cells. Expression of PD-L1 on tumors strongly correlates with the survival of cancer patients. PD-L1 on tumors interacts with the co-inhibitory molecule Programmed death receptor-1 (PD-1, CD279) on T cells mediating decreased TCR-mediated proliferation and cytokine production. In animal tumor models, blockade of PD-L1/PD-1 interactions resulted in an improved tumor control. In addition, exhausted T cells during chronic viral infections could be revived by PD-L1 blockade. Thus, targeting PD-L1/PD-1 interactions might improve the efficacy of adoptive cell therapies (ACT) of chronic infections as well as cancers. Obstacles for a general blockade of PD-L1 might be its role in mediating peripheral tolerance. This review discusses the currently available data concerning the role of PD-L1 in tumor immune evasion and envisions possibilities for implementation into ACT for cancer patients.

Animals↗