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PubMed1996

Effect of PD 098059, a specific inhibitor of mitogen-activated protein kinase kinase, on urokinase expression and in vitro invasion.

The elevated expression of the urokinase-type plasminogen activator gene, which is necessary for the invasive phenotype of several types of cancers, is controlled by growth factors such as epidermal growth factor, transforming growth factor a, and fibroblast growth factor which bind to and activate protein tyrosine kinase transmembrane receptors. Since these activated receptors communicate with the nucleus via a signaling pathway in which c-Raf-1, mitogen-activated protein kinase kinase 1 (MEK1), and the extracellular signal-regulated kinases are sequentially activated, we determined the effect of a specific MEK1 inhibitor (PD 098059) on urokinase expression in two squamous cell carcinoma cell lines (UM-SCC-1 and MDA-TU-138) characterized as avid secretors of the plasminogen activator. PD 098059 treatment of either cell line reduced the amount of secreted urokinase in a dose-dependent manner. In contrast, a compound (daidzein) chemically unrelated to PD 098059 had little effect on urokinase secretion. The effect of PD 098059 on urokinase secretion in UM-SCC-1 cells was reversible and correlated with decreased extracellular signal-regulated kinase 1 activity. PD 098059 caused a dose-dependent reduction in the in vitro invasiveness of UM-SCC-1 cells whereas it had little effect on proliferation rates. Transient transfection assays with a chloramphenicol acetyl transferase reporter driven by the urokinase promoter indicated that diminished secretion of the protease was largely a consequence of reduced promoter activity. These findings suggest that interfering with MEK1 may provide a novel means of controlling the invasiveness of tumors in which this signaling cascade is activated by autocrine and/or paracrine growth factors.

Carcinoma, Squamous Cell↗
PubMed1997

Appearance of morphologically abnormal Sertoli cells in infertile PD male rats during postnatal development.

Our previous studies using 12-week-old PD (pd/pd) male rats have indicated high incidence of morphologically abnormal Sertoli cells. Because sterility in these males is attributable to abnormal spermatogenesis, it is suggested that the abnormal Sertoli cells are related to abnormal spermatogenesis. In this study, the testes of prepubertal 7- and 21-day-old male pd/pd rats were examined ultrastructurally for the presence of abnormal Sertoli cells. The pd/+ males served as controls. At 7 days of age, light and dark types of Sertoli cells were found in pd/pd males. However, no anatomic abnormality existed in those cells. Cytoplasmic organelles were underdeveloped. The only difference between the light and dark Sertoli cells was the high electron density in the nucleus and cytoplasm of the dark cells. These features were similar between pd/pd and pd/+ males. At 21 days of age, the dark Sertoli cells had disappeared, and light Sertoli cells and abnormal Sertoli cells were observed in pd/pd males. The light Sertoli cells had well-developed cytoplasmic organelles. On the other hand, abnormal Sertoli cells had a dark appearance, irregularly shaped nuclei, and a large quantity of lipid droplets in the cytoplasm. These findings suggested the presence of functional disorders in lipid metabolism. The light and abnormal Sertoli cells also were found in pd/+ males; however, incidence of the abnormal Sertoli cells was significantly higher in pd/pd males (11.3%), compared with that in pd/+ males (4.9%). Thus, these results indicate that in pd/pd male rats, a number of abnormal Sertoli cells appear by 21 days of age.

Animals↗
PubMed1997

Efficiency of a silver ring in preventing exit-site infections in adult PD patients: results of the SIPROCE Study. Silver ring Prophylaxis of the Catheter Exit Site.

A randomized, multicenter clinical trial was conducted to evaluate the efficiency in preventing exit-site infection of a silver ring mounted on peritoneal dialysis (PD) catheter and placed at skin level (designed by Grosse-Siestrup, 1992). Eligible patients stratified by diabetes mellitus were monitored prospectively for 12 months using a detailed structured inventory. New patients starting PD treatment during the study period were followed for at least 3 months. Basic characteristics of the silver ring group (N = 86) and controls (N = 88) such as age, sex, S. aureus nasal carriage, type of PD catheter placement and catheter indwelling time, mode of PD, and number of connections for bag exchanges did not differ significantly between the two groups. Nineteen exit-site infections occurred in the silver ring group and 15 in the control group. The incidence of "equivocal" exit-site findings and time of improvement to a "good" or "perfect" exit site were similar in both groups. Kaplan-Meier analysis of the probability of an infection-free time interval revealed no statistically significant difference between subjects with the silver device and controls. In 6 of the 86 cases, displacement of the silver ring caused severe tunnel infection followed by catheter loss in 2. We conclude that the silver ring used in this setting is not effective in preventing exit-site infections in PD patients.

Bacterial Infections↗
PubMed1998

Early antibacterial effect of Pd-Ag dental alloy on aerobic and microaerophilic flora in oral cavity.

Early effect of Pd-Ag alloy on aerobic and microaerophilic flora from healthy oral cavity was studied. Normal microbial flora was sampled from saliva, dental plaque and gingival crevice from healthy individuals without any prosthodontic appliances or periodontal diseases. Such samples were inoculated into liquid media and were left in thermostat (37 degrees C) in aerobic condition. In some samples one or two sterile Pd-Ag alloy pieces were inoculated, while some samples were left without that pieces to be a control group. Both were kept in a thermostat for 24 and 48 hrs and after that were examined for bacterial dehydrogenic activity to reveal the amount of active bacteria in a sample. Dehydrogenic activity was registered after incubation of 0.1 ml of 3-phenyltetrazolynchloryde (TTC) into samples. TCC changes a colour of a liquid media because of bacterial dehydrogenic activity and therefore samples were analysed in a spectroscope. Statistical analysis revealed lower bacterial activity (lower TTC distinction) in samples with one or two Pd-Ag alloy pieces than in a control group. These results indicate the existence of initial inhibitory effect of Pd-Ag alloys on aerobic flora in the mouth, which might give space for anaerobic strains to increase ther growth. Presence of periodontal changes in a gingival crevice with Pd-Ag alloy crowns is probably due to anaerobic micro-organisms, as mostly anaerobic strains are responsible for periodontal disease.

Anti-Bacterial Agents↗
PubMed2026

Localized PD-1 CAR T therapy reprograms neuroinflammation.

B cell-depleting therapies are effective in multiple sclerosis (MS), yet some patients relapse, underscoring the need for more precise interventions. To identify new therapeutic targets, we generated a single-cell RNA sequencing (scRNA-seq) atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases. We found disease-associated enrichment of class-switched immunoglobulin G+ (IgG+) B cells and plasma cells in MS CSF. Unbiased analysis identified a rare disease-enriched subset of activated, T cell receptor (TCR)-restricted, PD-1+ T follicular helper-like cells with B cell-recruiting features. To target this population, we developed PD-1-directed chimeric antigen receptor (CAR) T cells that selectively depleted pathogenic PD-1+ CD4 T cells and locally released IL-10. This strategy attenuated central nervous system (CNS) inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models. These findings define a CNS-localized adaptive immune circuit in MS and nominate programmable PD-1 CAR T cells as a strategy to disrupt it.

Animals↗
PubMed2026

Proteomic and Metabolomic Analysis of Immune-Related Adverse Events in Patients Treated with PD-1 Inhibitors.

As a class of immune checkpoint inhibitors (ICIs), programmed cell death protein-1 (PD-1) blockade has demonstrated remarkable efficacy in the treatment of various malignancies. However, their clinical application is constrained by the high incidence of immune-related adverse events (irAEs), which arise from nonspecific immune activation and can affect multiple organ systems, with severe cases posing life-threatening risks. This study integrated high-throughput proteomic and metabolomic analyses to systematically characterize the molecular features associated with irAEs in cancer patients receiving PD-1 inhibitor therapy. The results showed that, following the first treatment, patients who developed irAEs exhibited potential involvement of the NF-κB pathway, along with lower baseline levels of SNRPA and higher expression of CD63. Metabolomic analyses further revealed that the kynurenine/tryptophan ratio was significantly elevated in the irAE group both at baseline and post-treatment compared with patients who did not develop irAEs. In addition, significant differences in the abundance of specific lipids were observed between the two groups prior to the administration of immunotherapy. Our findings provide exploratory insights into immune and metabolic alterations associated with PD-1 blockade treatment and may help generate hypotheses for future studies on early irAE risk assessment in cancer patients undergoing PD-1 blockade therapy.

Humans↗
PubMed2026

Targeting USP22 reprograms the tumor microenvironment and sensitizes KRAS/p53-driven lung cancer to anti-PD-1 immunotherapy.

RATIONALE: Ubiquitin-specific peptidase 22 (USP22), a deubiquitinase and component of the "Death-from-Cancer" 11-gene signature, is overexpressed in multiple malignancies and linked to recurrence, therapy resistance, and poor prognosis. Its role in KRAS/p53-driven lung cancer and the response to immune checkpoint inhibitors (ICIs) remains poorly defined. Here, we investigated USP22 as a potential therapeutic target in KRAS/p53-driven lung cancer. METHODS: A conditional Usp22 knockout (Usp22-KO) was generated in the KRASG12D; p53-/- (KP) mouse model. Cancer progression was monitored by micro-computed tomography (micro-CT). Multiplex immunofluorescence (mIF), RNA sequencing, and spatial transcriptomics profiled cancer and tumor microenvironment (TME) changes. Responses to anti-PD-1/PD-L1 therapies were compared between KP and Usp22-KO KP (KPU-) lung cancers. RESULTS: USP22 was highly expressed in early-stage KRAS/p53-driven mouse lung cancers and strongly correlated with proliferation marker Ki67. Usp22 deletion suppressed cancer growth, prolonged survival, and promoted cancer differentiation. Spatial transcriptomics and mIF revealed reduced CD206+ M2 macrophages, myeloid-derived suppressor cells (MDSCs), TGF-β1, and angiogenesis, along with increased functional CD8+ T cells. Mechanistically, USP22 regulated gene expression and protein stability, reducing c-Myc, PD-L1, TGF-β1, and SPARC upon Usp22 loss. Compared with KP cancer, KPU- and SPARC-knockdown KP cancers showed reduced macrophage chemotaxis and impaired basal- and TGF-β1-induced M2 polarization of RAW264.7 cells, suggesting that TGF-β1 and SPARC downregulation partially contributes to decreased M2 macrophage infiltration in KPU- cancers. Notably, Usp22 loss enhanced the efficacy of anti-PD-L1 and anti-PD-1 therapies in orthotopic and subcutaneous KP lung cancer models, respectively. USP22 and SPARC expression were also strongly correlated in human lung cancers. CONCLUSIONS: USP22 promotes progression and immune evasion in KRAS/p53-driven lung cancer. Targeting USP22 reprograms the TME, suppresses oncogenic signaling, and sensitizes tumors to ICI, establishing USP22 as a promising therapeutic target.

Animals↗
PubMed2026

Evolving Role of Immunotherapy in Advanced Esophageal Squamous Cell Carcinoma: Are Programmed Death-Ligand 1 (PD-L1) Cutoffs Still Relevant?

Immune checkpoint inhibitors have transformed the management of advanced esophageal squamous cell carcinoma (ESCC) across first-line, second-line, and perioperative settings. Programmed death-ligand 1 (PD-L1) expression has served as the principal biomarker guiding patient selection for these agents, yet it is measured inconsistently across trials and antibody platforms, and its predictive value has come under renewed scrutiny as follow-up data have matured. This review synthesizes the pivotal randomized trials that established anti-programmed cell death protein-1 therapy in ESCC, critically appraises the pooled and patient-level meta-analyses that have re-examined outcomes across biomarker subgroups, and situates recent regulatory reassessment of PD-L1 thresholds within this broader evidence base. Assay heterogeneity between scoring systems, discordance across antibody clones, and the biological distinction between PD-L1 as a prognostic versus a predictive marker are examined as sources of continued uncertainty. The review concludes by considering emerging genomic and microenvironmental biomarkers that may eventually complement or refine PD-L1-based patient selection, and offers a framework for interpreting a single expression threshold as an approximate, assay-dependent stratifier rather than a precise biological boundary.

combined positive score↗
PubMed2001

Size-selective electrochemical preparation of surfactant-stabilized Pd-, Ni- and Pt/Pd colloids.

A detailed study concerning the size-selective electrochemical preparation of R4N+Br- -stabilized palladium colloids is presented. Such colloids are readily accessible using a simple electrolysis cell in which the sacrificial anode is a commercially available Pd sheet, the surfactant serving as the electrolyte and stabilizer. It is shown that such parameters as solvent polarity, current density, charge flow, distance between electrodes and temperature can be used to control the size of the Pd nanoparticles in the range 1.2-5 nm. Characterization of the Pd colloids has been performed using transmission electron microscopy (TEM), small angle X-ray scattering (SAXS) and X-ray powder diffractometry (XRD) evaluated by Debye-function-analysis (DFA). Possible mechanisms of particle growth are discussed. Experiments directed towards the size-selective electrochemical fabrication of (n-C6H13)4N+Br- -stabilized nickel colloids are likewise described. Finally, a new strategy for preparing bimetallic colloids (e.g., Pt/Pd nanoparticles) electrochemically is presented, based on the use of a preformed colloid (e.g., (n-C8H17)4N+Br- -stabilized Pt particles) and a sacrificial anode (e.g., Pd sheet).

Journal Article↗
PubMed2007

Pt(0) and Pd(0) olefin complexes of the metalloid N-heterocyclic carbene analogues [E(I)(ddp)] (ddp=2-{(2,6-diisopropylphenyl)amino}-4-{(2,6-diisopropylphenyl)imino}-2-pentene; E=Al, Ga): ligand substitution, H--H and Si--H bond activation, and cluster formation.

Various products of the reaction of [E(ddp)] (ddp=2-{(2,6-diisopropylphenyl)amino}-4-{(2,6-diisopropylphenyl)imino}-2-pentene; E=Al, Ga) with Pt(0) and Pd(0) olefin complexes are reported. Thus, the reaction of [Pt(cod)(2)] (cod=1,5-cyclooctadiene) with two equivalents of [Ga(ddp)] yields [Pt(1,3-cod){Ga(ddp)}(2)] (1), whereas treatment of [Pd(2)(dvds)(3)] (dvds=1,1,3,3-tetramethyl1,3-divinyldisiloxane) with [E(ddp)] leads to the monomeric compounds [(dvds)Pd{E(ddp)}] (E=Ga (2 a), Al (2 b)) by substitution of the bridging dvds ligand. Both 1 and 2 a readily react with strong pi-acceptor ligands such as CO or tBuNC to give the dimeric compounds [M{mu(2)-Ga(ddp)}(L)] (L=CO, tBuNC; M=Pt (3 a, 5 a), Pd (3 b, 5 b)), respectively. Based on (1)H NMR spectroscopic data, [Pt{Ga(ddp)}(2)(CO)] is likely to be an intermediate in the formation of 3 a. Furthermore, reactions of 1 with H(2) and HSiEt(3) yield the monomeric compounds [Pt{Ga(ddp)}(2)(H)(2)] (7) and [Pt{Ga(ddp)}(2)(H)(SiEt(3))] (8). Finally, the reaction of [Pt(cod)(2)] with one equivalent of [Ga(ddp)] in the presence of H(2) in hexane gives the new dimeric cluster [Pt{mu(2)-Ga(ddp)}(H)(2)](2) (9).

Journal Article↗
PubMed2003

Gas-phase investigation of Pd(II)-alanine complexes with small native and derivatized peptides containing histidine.

We report here the generation of gas-phase complexes containing Pd(II), a ligand (deprotonated alanine, A-), and/or N-terminus derivatized peptides containing histidine as one of the amino acids. The species were produced by electrospray ionization, and their gas-phase reactions were investigated using ion-trap tandem mass spectrometry. Pd(II) forms a stable diaqua complex in the gas phase of the formula, [Pd(A-) (H(2)O)(2)]+, (where A- = deprotonated alanine) along with ternary complexes containing A- and peptide. The collision-induced dissociation (CID) patterns of the binary and ternary complexes were investigated, and the dissociation patterns for the ternary complexes suggest that: (a) the imidazole ring of the histidine side group may be the intrinsic binding site of the metal ion, and (b) the peptides fragment primarily by cleavage of the amide bond to the C-terminal side of the histidine residues. These observations are in accord with previous solution-state studies in which Pd(II) was shown to cause hydrolysis of an amide bond of a peptide at the same position.

Alanine↗
PubMed2006

Does seasonal variation affect hallucinations in PD? A longitudinal study.

The objective of this study was to examine the chronobiology of visual hallucinations in Parkinson's disease (PD) patients to test whether hallucinations are more severe during darker months (winter) than summer months. We extracted longitudinal data on the UPDRS Thought Disorder (TD) score, taken as part of regular patient management on sequential visits through a 1-year cycle in hallucinating PD patients. To reduce the confounding effects of medication adjustments, analysis was restricted to patients with a baseline evaluation that did not involve a medication change. The primary outcome was the seasonal change in hallucination severity, defined as a change in TD score or neuroleptic use. Using Wilcoxon rank-sum tests, we compared the exacerbation of hallucination by season, focusing on winter (December through February) versus summer (June through August). A total of 51 hallucinating patients met entry criteria, and their longitudinal data were analyzed. There was no difference in hallucination severity with changing season; the level of wintertime exacerbation was no greater than summertime exacerbation (P = 0.42). Although hallucinations frequently develop in dimmed environments and evening hours, the darkness of wintertime does not exacerbate hallucinations in PD subjects on stable medications. Because we found no evidence of seasonal variations, we cannot recommend phototherapy or other strategies affecting chronobiological systems as research priorities to treat PD hallucinations. (c) 2006 Movement Disorder Society.

Darkness↗
PubMed2026

Icaritin Sensitizes Hepatocellular Carcinoma to PD-L1 Therapy by NQO1-Dependent Ferroptosis Induction.

Hepatocellular carcinoma (HCC) remains challenging with limited immunotherapy response. Despite its clinical promise in advanced HCC, the mechanisms of icaritin, especially concerning ferroptosis induction and immune modulation, remain elusive. This study aims to determine if the antitumor effect of icaritin involves the induction of ferroptosis via NAD(P)H quinone oxidoreductase 1 (NQO1) and if it can augment the efficacy of programmed cell death 1 ligand 1 (PD-L1) therapy by potentiating natural killer (NK) cell activity. Using human HCC cell lines (Huh7, Hep3B, PLC/PRF/5, SNU-449, and MHCC97-H) and two synergistic mouse models (Hepa1-6 and SgPten/c-Met), we examined icaritin's inhibition of tumor growth and induction of ferroptosis via the NQO1 pathway, monitoring key markers (reactive oxygen species [ROS], glutathione peroxidase 4 [GPX4], ferritin heavy chain 1 [FTH1]). The NQO1 inhibitor dicoumarol was employed to validate the pathway. Tumor microenvironment (TME) remodeling was assessed through cancer-associated fibroblasts (CAFs) markers and immune cell profiling, focusing on NK cell infiltration. Combination therapy with anti-PD-L1 was tested in vivo. Icaritin significantly inhibited HCC growth in vitro and in vivo. Its antitumor effect was mediated by NQO1-mediated ferroptosis, via elevated ROS, diminished mitochondrial membrane potential, and downregulated GPX4 and FTH1. Analysis of The Cancer Genome Atlas (TCGA) data revealed that NQO1 is overexpressed in human HCC tissues. Icaritin enhanced NK cell infiltration while reducing CAF abundance and suppressing recombinant focal adhesion kinase (FAK) and discoidin domain receptor 1 (DDR1) signaling. Notably, icaritin synergized with anti-PD-L1 therapy to enhance tumor suppression without increasing toxicity, correlating with potentiated NK cell immunity. Our findings demonstrate that icaritin triggered NQO1-mediated ferroptosis and remodeled TME to enhance NK cell recruitment and PD-L1 therapy efficacy. This provides rationale for evaluating icaritin-based combination immunotherapy in HCC through dual action on ferroptosis and NK cell activation.

Ferroptosis↗
PubMed2006

Studies of gas-phase fragmentation reactions of [Pd(PPh3)2(OCOR)]+ by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry.

Gas-phase fragmentation reactions of [Pd(PPh3)2(OCOR)]+ (R = H, CH3, CD3, C2H5, n-C3H7, n-C6H13 and C6H5) were studied by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICRMS). In sustained off-resonance irradiation collision-activated dissociation (SORI-CAD) experiments, the complexes all dissociated to yield the same product ion at m/z 629.1. We propose that the fragmentation pathway occurs through the elimination of RCOOH and a palladium(IV) hydride intermediate. Semi-empirical (PM3) calculations shed light on the mechanism for the fragmentation reactions of these compounds. The results of deuterium-labeling experiments indicate that the protons of RCOOH lost from [Pd(PPh3)2(OCR)]+ originate from the phenyl in the triphenylphosphine ligand. [Pd(PPh3)2(OCOH)]+ undergoes two competitive pathways in SORI-CAD experiments, one of which is similar to that of [Pd(PPh3)2(OCOR)]+ (R = CH3, CD3, C2H5, n-C3H7, n-C6H13 and C6H5), and the other involves decarboxylation. The present study demonstrates that MS could play an important role in studying the gas-phase chemistry of palladium hydrides.

Journal Article↗
PubMed1993

Comparison of the effects of the cholecystokinin-B receptor antagonist, PD 134308, and the cholecystokinin-A receptor antagonist, L-364,718, on dopamine neuronal activity in the substantia nigra and ventral tegmental area.

Extracellular single-unit recording techniques were used to study the effects of the cholecystokinin-A (CCK-A) antagonist, L-364,718, and the CCK-B antagonist, PD 134308, on DA neuronal activity in chloral hydrate anesthetized rats. Neither L-364,718 (0.1-1.6 mg/kg i.v.) nor PD 134308 (0.1-6.4 mg/kg) altered the basal firing rate of substantia nigra or ventral tegmental area DA neurons. The ability of PD 134308 and L-364,718 to alter the apomorphine-induced inhibition of substantia nigra DA neurons was assessed. Pretreatment with L-364,718 (0.6 or 4.16 mg/kg i.v.) did not shift the apomorphine dose-response curve (0.5-32 micrograms/kg i.v.). In contrast, PD 134308 (0.6 or 6.4 mg/kg i.v.) produced dose-related, significant shifts to the right of the apomorphine dose-response curves. However, these effects were small in comparison to the haloperidol (0.1 mg/kg i.p.)-induced shift of the apomorphine curve. These data suggest that in the substantia nigra there may be a tonic level of CCK release that, through actions on CCK-B receptors, may modulate DA agonist-induced inhibition of DA neuronal activity.

Animals↗
PubMed1999

Hydrogenation of 1-Hexene and Hexadienes by Ultrafine Pd Particles Supported on the Surface of PrPO(4) Hollow Particles.

Novel fine polymer particles containing ultrafine Pd particles dispersed on the surface of core shell [core, poly(styrene-co-acrylic acid); shell, PrPO(4)]-type microspheres were prepared by the emulsifier-free emulsion polymerization of styrene with acrylic acid followed by the addition of PdCl(2) and a mixture of Pr(NO(3))(3) and NaH(2)PO(2). Pyrolysis of the resulting polymer particles at 900 degrees C provides organic polymer-free hollow particles (diameter, 473-586 nm) composed of Pd metal and PrPO(4). Hydrogenation of 1-hexene, trans-1,3-hexadiene, trans-1,4-hexadiene, and 1,5-hexadiene using the resulting Pd/PrPO(4) particles (reactant/Pd = 500 mol/mol) as catalyst revealed very high activity, especially for hydrogenations of 1-hexene and 1,5-hexadiene as compared with conventional Pd particles/Al(2)O(3) and Pd particles on powdered PrPO(4). Copyright 1999 Academic Press.

Journal Article↗
PubMed2006

Cortical muscle coupling in Parkinson's disease (PD) bradykinesia.

OBJECTIVES: To determine if novel methods establishing patterns in EEG-EMG coupling can infer subcortical influences on the motor cortex, and the relationship between these subcortical rhythms and bradykinesia. BACKGROUND: Previous work has suggested that bradykinesia may be a result of inappropriate oscillatory drive to the muscles. Typically, the signal processing method of coherence is used to infer coupling between a single channel of EEG and a single channel of rectified EMG, which demonstrates 2 peaks during sustained contraction: one, approximately 10 Hz, which is pathologically increased in PD, and a approximately 30 Hz peak which is decreased in PD, and influenced by pharmacological manipulation of GABAA receptors in normal subjects. MATERIALS AND METHODS: We employed a novel multiperiodic squeezing paradigm which also required simultaneous movements. Seven PD subjects (on and off L-Dopa) and five normal subjects were recruited. Extent of bradykinesia was inferred by reduced relative performance of the higher frequencies of the squeezing paradigm and UPDRS scores. We employed Independent Component Analysis (ICA) and Empirical Mode Decomposition (EMD) to determine EEG/EMG coupling. RESULTS: Corticomuscular coupling was detected during the continually changing force levels. Different components included those over the primary motor cortex (ipsilaterally and contralaterally) and over the midline. Subjects with greater bradykinesia had a tendency towards increased approximately 10 Hz coupling and reduced approximately 30 Hz coupling that was erratically reversed with L-dopa. CONCLUSIONS: These results suggest that lower approximately 10 Hz peak may represent pathological oscillations within the basal ganglia which may be a contributing factor to bradykinesia in PD.

Antiparkinson Agents↗
PubMed1986

Biological and biochemical activities of the novel antitumor antibiotic PD 114,759 and related derivatives.

A complex of novel and exceptionally potent antibiotics has been evaluated for antitumor activity in vitro and in vivo and characterized with regard to their ability to cause DNA strand scission. The major component, PD 114,759, was quite active against all in vitro tumor systems including the human tumors, MCF-7 breast, HCT-8 colon, and A549 lung and the murine tumors M16/c mammary, Lewis lung, Pan 02 pancreas and L1210 leukemia. ID50 values ranged from 2-57 pg/ml. In vivo this agent produced significant increases of host life spans in mice bearing L1210 leukemia, B16 melanoma and the M5076 sarcoma. Further, it inhibited growth of subcutaneous implants of the Ridgway osteogenic sarcoma by 80% and growth of the MX-1 human mammary xenograft by 90-95%. PD 114,759, however, had no activity against the colon adenocarcinoma 11a or mammary adenocarcinoma 16c. Chinese hamster ovary cells exposed for 24 hours to concentrations of PD 114,759 ranging from 18 to 37 pg/ml accumulated in the S and G2+M phases of the cell cycle with a corresponding decrease in G1. Higher concentrations of drug apparently stopped any progression through the cell cycle. PD 114,759 caused significant DNA single strand breaks in L1210 cells exposed for 1 hour to drug concentrations as low as 20 pg/ml and the frequency of these lesions increased in proportion to the drug concentration. A portion of these DNA breaks appeared to be associated with protein. In contrast, no double strand DNA breaks were detected at the highest drug concentration tested (100 pg/ml).

Animals↗