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PubMed2004

Cardiac 123I-MIBG scintigraphy can assess the disease severity and phenotype of PD.

OBJECTIVE: Cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphy studies of patients with idiopathic Parkinson's disease (PD) found decreased uptake. Whether this decrease is associated with clinical severity as assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) and the phenotypes of PD has not been determined. METHODS: Cardiac MIBG scintigraphy was performed on 34 patients with PD, 7 with multiple system atrophy (MSA), 4 with dementia with Lewy bodies (DLB), and 11 normal controls (NCs). Early and delayed MIBG heart/mediastinum (H/M) ratios were evaluated. PD severity was assessed by the Hoehn and Yahr (H-Y) stage and UPDRS. Patients were grouped in two phenotypes, tremor and postural instability gait difficulty (PIGD)-dominant groups based on UPDRS components. Associations between MIBG uptake and age at onset, UPDRS, and disease phenotype were analyzed in each group. RESULTS: The early H/M ratio was significantly lower in patients with PD (1.45+/-0.207) than in the NCs (2.08+/-0.231), and in those with MSA (1.99+/-0.284), but not in those with DLB (1.29+/-0.0435). The delayed H/M ratio for PD (1.33+/-0.276) also was significantly decreased as compared to the ratios for NCs (2.17+/-0.286) and MSA (2.16+/-0.414) but not DLB (1.16+/-0.0949). The early H/M ratio was significantly correlated with both UPDRS score and age at onset, whereas the delayed H/M ratio only was significantly correlated with age at onset. The PIGD-dominant group had significantly higher UPDRS scores and lower H/M ratios than the tremor-dominant group. CONCLUSION: Cardiac MIBG scintigraphy can be used to differentiate PD from MSA and NC, and to determine the disease severity and phenotypes of PD.

3-Iodobenzylguanidine↗
PubMed2006

Rasagiline-associated motor improvement in PD occurs without worsening of cognitive and behavioral symptoms.

BACKGROUND: Cognitive and behavioral adverse events (AEs) such as hallucinations, confusion, depression, somnolence and other sleep disorders commonly limit effective management of motor symptoms in PD. Rasagiline (N-propargyl-1(R)-aminoindan) mesylate is a novel, second-generation, selective, irreversible monoamine oxidase type B inhibitor, demonstrated in monotherapy and adjunctive trials to be effective for PD with excellent tolerability. METHODS: The occurrence of cognitive and behavioral AEs and the change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS) part I mental subscores were reviewed in two multicenter, randomized, placebo-controlled, 26-week trials of rasagiline for early and moderate-to-advanced patients with PD. The UPDRS is a multi-item rating scale specific to PD; part I rates the patient's intellectual impairment, thought disorders, depression and motivation/initiative. RESULTS: The TEMPO study evaluated rasagiline monotherapy in early PD patients (n=404). The PRESTO study evaluated rasagiline as adjunctive therapy in moderate-to-advanced PD patients with motor complications who were receiving optimized levodopa/carbidopa (n=472). In the analysis of adverse event reporting for both studies, no cognitive and behavioral AE in either the rasagiline 1 mg or placebo groups exceeded 10% of the study population and the frequency differences between rasagiline 1 mg and placebo never exceeded 3%. There was no adverse effect on the UPDRS mental subscore relative to placebo in either of the two studies. CONCLUSION: Rasagiline 1 mg once daily improves PD symptoms and motor fluctuations in early and moderate-to-advanced PD patients without causing significant cognitive and behavioral AE or adverse changes in mentation, behavior and mood.

Aged↗
PubMed1997

The pharmacology of the novel and selective sigma ligand, PD 144418.

The pharmacology of PD 144418 (1-propyl-5-(3-p-tolyl-isoxazol-5-yl)-1,2,3,6-tetrahydropyridine) was characterized using neurochemical, biochemical and behavioral techniques. For sigma (sigma 1 and sigma 2 respectively) sites, PD 144418 affinities were determined using whole guinea pig brain membranes with [3H](+)-pentazocine and neuroblastoma x glioma cell membranes using [3H]1,3,di-O-tolylguanidine (DTG) in the presence of 200 nM (+)-pentazocine. PD 144418 exhibited an affinity for sigma 1 of 0.08 nM (Ki) versus a K1 of 1377 nM for sigma 2 site. Additional receptor binding studies indicated that PD 144418 lacked affinity for dopaminergic, adrenergic, muscarinic and a variety of other receptors. In vitro studies indicated that PD 144418 reversed the N-methyl-D-aspartate (NMDA)-induced increase in cyclic GMP (cGMP) in rat cerebellar slices without affecting the basal levels, suggesting that sigma 1 sites may be important in the regulation of glutamine-induced actions. PD 144418 potentiated the decrease in 5-hydroxytryptophan caused by haloperidol in the mesolimbic region, but by itself had no effect in 5-hydroxytrypamine (5-HT) and dopamine (DA) synthesis. Behaviorally, similar to other sigma ligands, PD 144418 antagonized mescaline-induced scratching at doses that did not alter spontaneous motor activity. This action is suggestive of potential antipsychotic property. It exhibited no anxiolytic and antidepressant properties in the models used. These results show that PD 144418 is a very selective sigma 1 agent, devoid of any significant affinity for other receptors and that sigma 1 site may modulate actions in the CNS.

Animals↗
PubMed2001

Inhibition of the early phase of HIV replication by an isothiazolone, PD 161374.

A new class of substituted 2'-benzisothiazolone represented by PD 161374 was discovered with antiviral activity against retroviruses similar to previously described nucleocapsid inhibitor PD 159206 (DIBA-4). In T cell culture, the 50% inhibitory concentrations (EC(50)) of PD 161374 and PD 159206 were on average 2.5 microM (ranges of 1.2-13.5 microM) without any cytotoxic effect up to 100 microM. PD 161374 inhibited acute HIV infection and it was effective when added during the early phase of HIV infection. However, very modest effects were observed in chronically infected H9 cells and the HIV latency model line OM-10.1. Direct PCR analysis of infected cells demonstrated that PD 161374 delayed the appearance of completed HIV-cDNA products including 2LTR circles. Together all these results suggest that PD 161374 exerts its antiviral effect at pre-integration steps in the early phase of the virus life cycle. When combined with a protease inhibitor, PD 161374 did not show any antagonism and combination with a reverse transcriptase inhibitor (AZT) resulted in a synergistic effect.

Anti-HIV Agents↗
PubMed2003

Trinuclear heterobimetallic complexes with binucleating dithioxamides: stereoselective synthesis and solution behavior involving Pd-N bond rupture.

Bischelate platinum(II) complexes of the type [Pt(H-R(2)-N(2)C(2)S(2))(2)] (H-R(2)-N(2)C(2)S(2)(-) = dialkyl-dithioxamidate) are ditopic receptors which, after coordination of the first Pd(eta(3)-allyl)(+) moiety, induce the orientation of the second palladium-allyl fragment. Thus, a series of trimetallic complexes of formula bis-[(eta(3)-allyl)-palladium(II)](mu-bis-dialkyl-dithioxamidate-platinum(II) kappa-S,S-kappa-S',S'-Pt-kappa-N,N-Pd-kappa-N',N'-Pd') has been prepared in which the allyl fragments are oriented toward the same side of the molecular plane. We have also prepared the trimetallic complex using a dithioxamide obtained from the racemic phenylethylamine. Only two isomers were produced in equimolar ratio: the racemate that has four homochiral alkyl substituents and the mesoform containing the meso-dithioxamide that has homochiral substituents on the same side of molecular plane. Under the effect of the temperature, the trimetallic Pd-Pt-Pd complexes undergo rapid allyl isomerization; the mechanism of the isomerization, which is similar to that found by us in an analogue Pt-Pd bimetallic complex, is discussed. The crystal and molecular structure of bis-[(eta(3)-allyl)-palladium(II)](mu-bis-[S]-phenylethyl-dithioxamidate-platinum(II) kappa-S,S-kappa-S',S'-Pt-kappa-N,N-Pd-kappa-N',N'-Pd') has been reported.

Journal Article↗
PubMed1996

Theoretical Modeling of Water Exchange on [Pd(H(2)O)(4)](2+), [Pt(H(2)O)(4)](2+), and trans-[PtCl(2)(H(2)O)(2)].

Density functional theory is applied to modeling the exchange in aqueous solution of H(2)O on [Pd(H(2)O)(4)](2+), [Pt(H(2)O)(4)](2+), and trans-[PtCl(2)(H(2)O)(2)]. Optimized structures for the starting molecules are reported together with trigonal bipyramidal (tbp) systems relevant to an associative mechanism. While a rigorous tbp geometry cannot by symmetry be the actual transition state, it appears that the energy differences between model tbp structures and the actual transition states are small. Ground state geometries calculated via the local density approximation (LDA) for [Pd(H(2)O)(4)](2+) and relativistically corrected LDA for the Pt complexes are in good agreement with available experimental data. Nonlocal gradient corrections to the LDA lead to relatively inferior structures. The computed structures for analogous Pd and Pt species are very similar. The equatorial M-OH(2) bonds of all the LDA-optimized tbp structures are predicted to expand by 0.25-0.30 Å, while the axial bonds change little relative to the planar precursors. This bond stretching in the transition state counteracts the decrease in partial molar volume caused by coordination of the entering water molecule and can explain qualitatively the small and closely similar volumes of activation observed. The relatively higher activation enthalpies of the Pt species can be traced to the relativistic correction of the total energies while the absolute DeltaH() values for exchange on [Pd(H(2)O)(4)](2+) and [Pt(H(2)O)(4)](2+) are reproduced using relativistically corrected LDA energies and a simple Born model for hydration. The validity of the latter is confirmed via some simple atomistic molecular mechanics estimates of the relative hydration enthalpies of [Pd(H(2)O)(4)](2+) and [Pd(H(2)O)(5)](2+). The computed DeltaH() values are 57, 92, and 103 kJ/mol compared to experimental values of 50(2), 90(2), and 100(2) kJ/mol for [Pd(H(2)O)(4)](2+), [Pt(H(2)O)(4)](2+), and trans-[PtCl(2)(H(2)O)(2)], respectively. The calculated activation enthalpy for a hypothetical dissociative water exchange at [Pd(H(2)O)(4)](2+) is 199 kJ/mol. A qualitative analysis of the modeling procedure, the relative hydration enthalpies, and the zero-point and finite temperature corrections yields an estimated uncertainty for the theoretical activation enthalpies of about 15 kJ/mol.

Journal Article↗
PubMed2004

Homogeneous palladium catalyst suppressing Pd black formation in air oxidation of alcohols.

In homogeneous catalyst systems, there is the persistent problem that metal aggregation and precipitation cause catalyst decomposition and considerable loss of catalytic activity. Pd black formation is a typical example. Pd catalysts are known to easily aggregate and form Pd black, although they realize a wide variety of useful reactions in organic synthesis. In order to overcome this intrinsic problem of homogeneous Pd catalysis, we explored a new class of Pd catalyst by adopting aerobic oxidation of alcohols as a probe reaction. Herein we report a new catalyst system that suppresses the Pd black formation even under air and with a high substrate to catalyst molar ratio (S/C: more than 1000) in oxidation of alcohols. The novel pyridine derivatives having a 2,3,4,5-tetraphenylphenyl substituent and its higher dendritic unit at the 3-position of the pyridine ring were found to be excellent ligands with Pd(OAc)2 in the palladium-catalyzed air (balloon) oxidation of alcohols in toluene at 80 degrees C. Comparison with structurally related pyridine ligands revealed that introduction of the 2,3,4,5-tetraphenylphenyl substituent at the 3-position of pyridine ring effectively suppresses the Pd black formation, maintaining the catalytic activity for a long time to give aldehydes or ketones as products in high yields.

Journal Article↗
PubMed2003

Facile fabrication of Ag-Pd bimetallic nanoparticles in ultrathin TiO(2)-gel films: nanoparticle morphology and catalytic activity.

Ag-Pd bimetallic nanoparticles were prepared directly in ultrathin TiO(2)-gel films by a stepwise ion-exchange/reduction approach. Ion-exchange sites were created in ultrathin films using Mg(2+) ions as template. Ag(+) ion was then incorporated by ion exchange, and converted into metallic nanoparticles by low-temperature H(2) plasma, regenerating ion-exchange sites. The same procedure was then carried out for Pd(2+) ion, producing Pd-on-Ag bimetallic nanoparticles, as TEM observation and plasmon resonance absorption indicate. By contrast, reversed metal incorporation procedure appeared to give a mixture of individual Ag and Pd nanoparticles, as confirmed by TEM, absorption spectroscopy and X-ray photoelectron spectroscopy. For hydrogenation of methyl acrylate, the catalytic activity of the Pd-on-Ag nanoparticle is 367 times as large as that of commercial Pd black and 1.6 times as large as that of Pd monometallic nanoparticle. The outstanding catalytic activity was explicable by the large fraction of the surface-exposed Pd atoms. The formation process of the bimetallic nanoparticle and their general morphological feature are discussed.

Journal Article↗
PubMed2004

CH3O decomposition on PdZn(111), Pd(111), and Cu(111). A theoretical study.

Methanol steam re-forming, catalyzed by Pd/ZnO, is a potential hydrogen source for fuel cells, in particular in pollution-free vehicles. To contribute to the understanding of pertinent reaction mechanisms, density functional slab model studies on two competing decomposition pathways of adsorbed methoxide (CH(3)O) have been carried out, namely, dehydrogenation to formaldehyde and C-O bond breaking to methyl. For the (111) surfaces of Pd, Cu, and 1:1 Pd-Zn alloy, adsorption complexes of various reactants, intermediates, transition states, and products relevant for the decomposition processes were computationally characterized. On the surface of Pd-Zn alloy, H and all studied C-bound species were found to prefer sites with a majority of Pd atoms, whereas O-bound congeners tend to be located on sites with a majority of Zn atoms. Compared to Pd(111), the adsorption energy of O-bound species was calculated to be larger on PdZn(111), whereas C-bound moieties were less strongly adsorbed. C-H scission of CH(3)O on various substrates under study was demonstrated to proceed easier than C-O bond breaking. The energy barrier for the dehydrogenation of CH(3)O on PdZn(111) (113 kJ mol(-)(1)) and Cu(111) (112 kJ mol(-)(1)) is about 4 times as high as that on Pd(111), due to the fact that CH(3)O interacts more weakly with Pd than with PdZn and Cu surfaces. Calculated results showed that the decomposition of methoxide to formaldehyde is thermodynamically favored on Pd(111), but it is an endothermic process on PdZn(111) and Cu(111) surfaces.

Adsorption↗
PubMed2006

PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.

Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.

Antigens, CD↗
PubMed1997

Pediocin PD-1, a bactericidal antimicrobial peptide from Pediococcus damnosus NCFB 1832.

Pediocin PD-1, produced by Pediococcus damnosus NCFB 1832, is inhibitory to several food spoilage bacteria and food-borne pathogens. However, pediocin PD-1 is not active against other Pediococcus spp. and differs in this respect to other pediocins produced by Pediococcus acidilactici and Pediococcus pentosaceus. Production of pediocin PD-1 starts during early growth and reaches-a plateau at the end of exponential growth. Pediocin PD-1 was partially purified and its size was determined by tricine-SDS-PAGE as approximately 3.5 kDa. The isoelectric point (pI) of pediocin PD-1 is approximately 3.5, as determined with the Rotofor electrofocusing cell (BioRad). Pediocin PD-1 is heat-resistant (10 min at 121 degrees C) and remains active after 30 min of incubation at pH 2-10. Pediocin PD-1 is resistant to treatment with pepsin, papain, alpha-chemotrypsin and trypsin, but not Proteinase K. Pediocin PD-1 is bactericidal against sensitive cells of Oenococcus oeni (previously Leuconostoc oenos).

Bacteriocins↗
PubMed2001

Is Parkinson's disease the heterozygote form of Wilson's disease: PD = 1/2 WD?

Wilson's disease (WD) patients often present with Parkinson's disease (PD). Furthermore, most patients with PD have reduced ceruloplasmin, a characteristic of Wilson's disease. WD is an autosomal recessive disease (requires two faulty copies of a gene to produce a homozygote individual) that afflicts 1 in 1000 people. However, the number of people with one faulty copy (heterozygotes) is much larger, probably about 2% of the population. I hypothesize that the large number of heterozygotes for WD are at greatly increased risk for idiopathic PD, because these people accumulate free copper in the basal ganglia at a slower rate than homozygotes, which accounts for the fact that PD usually develops after 40 years of age. In WD, a ceruloplasmin deficiency results in accumulation of free Cu in the liver, brain, kidneys, etc. The excess Cu results in impaired Zn absorption, which would account for the low levels of Zn in the brains of PD patients. Moreover, the high levels of Fe found in the substantia nigra of PD patients may perhaps be explained by free Cu binding to iron binding protein-1 (IBP-1), causing it to malfunction and preventing it from detaching itself from the transferrin receptor (TfR) inhibition gene, resulting in expression of TfR even when the cell has plenty of Fe. The gradual accumulation of Fe and Cu would explain the damage inflicted on the substantia nigra by free radicals catalyzed by these two metals and which is exacerbated by the low levels of CuZnSOD, due to the Zn deficiency mentioned above. Moreover, if this hypothesis is correct, then PD could be used to help discover the gene (or genes) responsible for WD and vice versa. Furthermore, idiopathic PD could be prevented by identifying the heterozygote individuals and providing them with Zn supplementation, Cu chelation therapy and phlebotomy to eliminate Fe.

Copper↗
PubMed2005

Adsorption of carbon on Pd clusters of nanometer size: a first-principles theoretical study.

Adsorbed atomic C species can be formed in the course of surface reactions and commonly decorate metal catalysts. We studied computationally C adsorption on Pd nanoclusters using an all-electron scalar relativistic density functional method. The metal particles under investigation, Pd(55), Pd(79), Pd(85), Pd(116), Pd(140), and Pd(146), were chosen as fragments of bulk Pd in the form of three-dimensional octahedral or cuboctahedral crystallites, exposing (111) and (100) facets as well as edge sites. These cluster models are shown to yield size-converged adsorption energies. We examined which surface sites of these clusters are preferentially occupied by adsorbed C. According to calculations, surface C atoms form strongly adsorbed carbide species (with adsorption energies of more than 600 kJ mol(-1)) bearing a significant negative charge. Surface sites allowing high, fourfold coordination of carbon are overall favored. To avoid effects of adsorbate-adsorbate interaction in the cluster models for carbon species in the vicinity of cluster edges, we reduced the local symmetry of selected adsorption complexes on the nanoclusters by lowering the global symmetry of the nanocluster models from point group O(h) to D(4h). On (111) facets, threefold hollow sites in the center are energetically preferred; adsorbed C is calculated to be slightly less stable when displaced to the facet borders.

Journal Article↗
PubMed2003

Molecular characterization of the 1,3-propanediol (1,3-PD) operon of Clostridium butyricum.

The genes encoding the 1,3-propanediol (1,3-PD) operon of Clostridium butyricum VPI1718 were characterized from a molecular and a biochemical point of view. This operon is composed of three genes, dhaB1, dhaB2, and dhaT. When grown in a vitamin B12-free mineral medium with glycerol as carbon source, Escherichia coli expressing dhaB1, dhaB2, and dhaT produces 1,3-PD and high glycerol dehydratase and 1,3-PD dehydrogenase activities. dhaB1 and dhaB2 encode, respectively, a new type of glycerol dehydratase and its activator protein. The deduced proteins DhaB1 and DhaB2, with calculated molecular masses of 88,074 and 34,149 Da, respectively, showed no homology with the known glycerol dehydratases that are all B12 dependent but significant similarity with the pyruvate formate lyases and pyruvate formate lyases activating enzymes and their homologues. The 1,158-bp dhaT gene codes for a 1,3-PD dehydrogenase with a calculated molecular mass of 41,558 Da, revealing a high level of identity with other DhaT proteins from natural 1,3-PD producers. The expression of the 1,3-PD operon in C. butyricum is regulated at the transcriptional level, and this regulation seems to involve a two-component signal transduction system DhaASDhaA, which may have a similar function to DhaR, a transcriptional regulator found in other natural 1,3-PD producers. The discovery of a glycerol dehydratase, coenzyme B12 independent, should significantly influence the development of an economical vitamin B12-free biological process for the production of 1,3-PD from renewable resources.

Alcohol Dehydrogenase↗
PubMed2001

PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine.

PD-1 is an immunoreceptor that belongs to the immunoglobulin (Ig) superfamily and contains two tyrosine residues in the cytoplasmic region. Studies on PD-1-deficient mice have shown that PD-1 plays critical roles in establishment and/or maintenance of peripheral tolerance, but the mode of action is totally unknown. To study the molecular mechanism for negative regulation of lymphocytes through the PD-1 receptor, we generated chimeric molecules composed of the IgG Fc receptor type IIB (Fc gamma RIIB) extracellular region and the PD-1 cytoplasmic region and expressed them in a B lymphoma cell line, IIA1.6. Coligation of the cytoplasmic region of PD-1 with the B cell receptor (BCR) in IIA1.6 transformants inhibited BCR-mediated growth retardation, Ca(2+) mobilization, and tyrosine phosphorylation of effector molecules, including Ig beta, Syk, phospholipase C-gamma 2 (PLC gamma 2), and ERK1/2, whereas phosphorylation of Lyn and Dok was not affected. Mutagenesis studies indicated that these inhibitory effects do not require the N-terminal tyrosine in the immunoreceptor tyrosine-based inhibitory motif-like sequence, but do require the other tyrosine residue in the C-terminal tail. This tyrosine was phosphorylated and recruited src homology 2-domain-containing tyrosine phosphatase 2 (SHP-2) on coligation of PD-1 with BCR. These results show that PD-1 can inhibit BCR signaling by recruiting SHP-2 to its phosphotyrosine and dephosphorylating key signal transducers of BCR signaling.

Animals↗
PubMed2006

PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection.

Here, we report on the expression of programmed death (PD)-1 on human virus-specific CD8(+) T cells and the effect of manipulating signaling through PD-1 on the survival, proliferation, and cytokine function of these cells. PD-1 expression was found to be low on naive CD8(+) T cells and increased on memory CD8(+) T cells according to antigen specificity. Memory CD8(+) T cells specific for poorly controlled chronic persistent virus (HIV) more frequently expressed PD-1 than memory CD8(+) T cells specific for well-controlled persistent virus (cytomegalovirus) or acute (vaccinia) viruses. PD-1 expression was independent of maturational markers on memory CD8(+) T cells and was not directly associated with an inability to produce cytokines. Importantly, the level of PD-1 surface expression was the primary determinant of apoptosis sensitivity of virus-specific CD8(+) T cells. Manipulation of PD-1 led to changes in the ability of the cells to survive and expand, which, over several days, affected the number of cells expressing cytokines. Therefore, PD-1 is a major regulator of apoptosis that can impact the frequency of antiviral T cells in chronic infections such as HIV, and could be manipulated to improve HIV-specific CD8(+) T cell numbers, but possibly not all functions in vivo.

Antigens, CD↗
PubMed2004

PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells.

Since metastasis is the major cause of death for cancer patients, there is an urgent need to develop new therapies to control hematogenous dissemination of cancer cells. Previously we and others demonstrated a novel mechanism that allows tumors to escape from the host immune response by expressing PD-L1 which can negatively regulate immune response through the interaction with PD-1, an immunoinhibitory receptor belonging to the CD28 family. In this study, we report that hematogenous spread of poorly immunogenic B16 melanoma cells to the liver was inhibited in PD-1-deficient mice. After inoculation to spleen, PD-L1 was induced on tumor cells, which did not express PD-L1 in vitro. As compared with wild-type mice, intrasplenic injection of B16 cells into PD-1-deficient mice showed enhanced induction of effector T cells in spleen, prolonged T cell proliferation and cytokine production, and augmented homing of effector T cells to tumor sites in the liver, resulting in accumulation of effector T cells in the tumor sites. PD-1 blockade by genetic manipulation or antibody treatment inhibited not only hematogenous dissemination of B16 melanoma cells to the liver on the C57BL/6 background, but also dissemination of CT26 colon cancer cells to the lung on the BALB/c background. These results suggest that PD-1 blockade may be a powerful tool for treatment of hematogenous spread of various tumor cells.

Animals↗
PubMed1992

In-vitro activity of PD 131628, a new quinolone antimicrobial agent.

The in-vitro activity of PD 131628, the active metabolite of the prodrug PD 131112, was compared with that of ciprofloxacin and members of other groups of antimicrobial agents against 701 recent clinical isolates and strains with known mechanisms of resistance. The MIC90s of PD 131628 against the Enterobacteriaceae were between 0.008 and 0.5 mg/L; PD 131628 was one- to four-fold more active than ciprofloxacin against these strains and was four-fold more active than ciprofloxacin against Pseudomonas aeruginosa. Against the Gram-positive species tested, PD 131628 was two- to four-fold more active than ciprofloxacin, inhibiting all strains of Staphylococcus aureus and Streptococcus pneumoniae with 0.5 mg/L or less. PD 131628 was very active against Neisseria spp., Haemophilus influenzae and Moraxella catarrhalis, with MIC90s ranging from 0.004 to 0.008 mg/L. Organisms with decreased susceptibility to other quinolones had decreased susceptibility to PD 131628, but there was no cross-resistance between this class of antimicrobial and other classes. The protein binding of PD 131628 was at most 25% across a broad range of concentrations. The addition of 70% human serum had little effect on the MICs, but caused a two- to eight-fold increase in MBCs.

Anti-Infective Agents↗