Intra-Tumoral Pharmacokinetics of Pazopanib in Combination with Radiotherapy in Patients with Non-Metastatic Soft-Tissue Sarcoma

There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is the best surrogate for pharmacokinetic and pharmacodynamic evaluation. Therefore, we aimed to quantify pazopanib concentrations in tumor tissue, to assess the correlation between tumor concentrations and plasma concentrations and between tumor concentrations and efficacy. In this clinical trial, non-metastatic STS patients were treated with neo-adjuvant concurrent radiotherapy and pazopanib. Plasma samples and tumor biopsies were collected, and pazopanib concentrations were measured using liquid chromatography-tandem mass spectrometry. Twenty-four evaluable patients were included. The median pazopanib tumor concentration was 19.2 µg/g (range 0.149–200 µg/g). A modest correlation was found between tumor concentrations and plasma levels of pazopanib (ρ = 0.41, p = 0.049). No correlation was found between tumor concentrations and percentage of viable tumor cells (p > 0.05); however, a trend towards less viable tumor cells in patients with high pazopanib concentrations in tumor tissue was observed in a categorical analysis. Possible explanations for the lack of correlation might be heterogeneity of the tumors and timing of the biopsy procedure.

Download Full-text

Parallel Reduction of Plasma Levels of High and Low Molecular Weight Kininogen in Patients with Cirrhosis

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614849 ◽

1999 ◽

Vol 82 (11) ◽

pp. 1428-1432 ◽

Cited By ~ 9

Author(s):

Cheryl Scott ◽

Francesco Salerno ◽

Elettra Lorenzano ◽

Werner Müller-Esterl ◽

Angelo Agostoni ◽

...

Keyword(s):

Molecular Weight ◽

Liver Disease ◽

Liver Function ◽

Plasma Levels ◽

Plasma Concentrations ◽

Normal Subjects ◽

Low Molecular Weight ◽

Major Band ◽

Sds Page ◽

Normal Controls

SummaryLittle is known about the regulation of high-molecular-weight-kininogen (HK) and low-molecular-weight-kininogen (LK) or the relationship of each to the degree of liver function impairment in patients with cirrhosis. In this study, we evaluated HK and LK quantitatively by a recently described particle concentration fluorescence immunoassay (PCFIA) and qualitatively by SDS PAGE and immunoblotting analyses in plasma from 33 patients with cirrhosis presenting various degrees of impairment of liver function. Thirty-three healthy subjects served as normal controls. Patients with cirrhosis had significantly lower plasma levels of HK (median 49 μg/ml [range 22-99 μg/ml]) and LK (58 μg/ml [15-100 μg/ml]) than normal subjects (HK 83 μg/ml [65-115 μg/ml]; LK 80 μg/ml [45-120 μg/ml]) (p < 0.0001). The plasma concentrations of HK and LK were directly related to plasma levels of cholinesterase (P < 0.0001) and albumin (P < 0.0001 and P < 0.001) and inversely to the Child-Pugh score (P < 0.0001) and to prothrombin time ratio (P < 0.0001) (reflecting the clinical and laboratory abnormalities in liver disease). Similar to normal individuals, in patients with cirrhosis, plasma HK and LK levels paralleled one another, suggesting that a coordinate regulation of those proteins persists in liver disease. SDS PAGE and immunoblotting analyses of kininogens in cirrhotic plasma showed a pattern similar to that observed in normal controls for LK (a single band at 66 kDa) with some lower molecular weight forms noted in cirrhotic plasma. A slight increase of cleavage of HK (a major band at 130 kDa and a faint but increased band at 107 kDa) was evident. The increased cleavage of HK was confirmed by the lower cleaved kininogen index (CKI), as compared to normal controls. These data suggest a defect in hepatic synthesis as well as increased destructive cleavage of both kininogens in plasma from patients with cirrhosis. The decrease of important regulatory proteins like kininogens may contribute to the imbalance in coagulation and fibrinolytic systems, which frequently occurs in cirrhotic patients.

Download Full-text

Plasma Thrombospondin as an Indicator of Intravascular Platelet Activation in Patients with Vasculitis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646003 ◽

1987 ◽

Vol 58 (03) ◽

pp. 850-852 ◽

Cited By ~ 15

Author(s):

M B McCrohan ◽

S W Huang ◽

J W Sleasman ◽

P A Klein ◽

K J Kao

Keyword(s):

Platelet Activation ◽

Plasma Levels ◽

Half Life ◽

Degradation Products ◽

Plasma Concentrations ◽

Primary Source ◽

Positive Correlation ◽

Activation Marker ◽

Fibrin Degradation Products ◽

The Mean

SummaryThe use of plasma thrombospondin (TSP) concentration was investigated as an indicator of intravascular platelet activation. Patients (n = 20) with diseases that have known vasculitis were included in the study. The range and the mean of plasma TSP concentrations of patients with vasculitis were 117 ng/ml to 6500 ng/ml and 791±1412 ng/ml (mean ± SD); the range and the mean of plasma TSP concentrations of control individuals (n = 33) were 13 ng/ml to 137 ng/ml and 59±29 ng/ml. When plasma TSP concentrations were correlated with plasma concentrations of another platelet activation marker, β-thromboglobulin (P-TG), it was found that the TSP concentration inei eased exponentially as the plasma β-TG level rose. A positive correlation between plasma levels of plasma TSP and serum fibrin degradation products was also observed. The results suggest that platelets are the primary source of plasma TSP in patients with various vasculitis and that plasma TSP can be a better indicator than β-TG to assess intravascular platelet activation due to its longer circulation half life.

Download Full-text

Elevated Circulating P-Selectin in Insulin Dependent Diabetes Mellitus

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650578 ◽

1996 ◽

Vol 76 (03) ◽

pp. 328-332 ◽

Cited By ~ 66

Author(s):

Bernd Jilma ◽

Peter Fasching ◽

Christine Ruthner ◽

Anna Rumplmayr ◽

Sabine Ruzicka ◽

...

Keyword(s):

Diabetes Mellitus ◽

Plasma Levels ◽

Plasma Concentrations ◽

Insulin Dependent Diabetes Mellitus ◽

Interquartile Range ◽

Insulin Dependent Diabetes ◽

Dependent Diabetes Mellitus ◽

Intergroup Comparison ◽

Median Plasma ◽

Insulin Dependent

SummaryBased on findings that showed increased P-selectin expression on platelets and on choroidal microvessels of patients with insulin dependent diabetes mellitus (IDDM), we hypothesized that also plasma concentrations of circulating (c)P-selectin would be increased in these patients.The aim of this study was to compare the plasma levels of cP-selec-tin between non-smoking patients with IDDM, treated with an intensified insulin therapy, and healthy controls. The study design was prospective, cross-sectional and analyst-blinded. Subjects were matched individually for sex, age and body mass index. Plasma levels of cP-selectin and of von Willebrand antigen (vWF-Ag) were determined by enzyme linked immunoassays.Forty-two pairs were available for intergroup comparison. Median plasma concentrations of cP-selectin in patients with IDDM (285 ng/ml; interquartile range: 233-372) were on average 21% higher than those of controls (236 ng/ml; interquartile range: 175-296; p = 0.004). Also, median plasma levels of vWF-Ag were 10% higher in patients (96 U/dl; interquartile range: 82-127) than controls (87 U/dl; interquartile range: 70-104; p = 0.025). There was no correlation between plasma concentrations of cP-selectin and vWF-Ag levels in either group (p ώ0.05).In conclusion, our results of increased cP-selectin levels are in line with increased P-selectin expression on platelets and on choroidal microvessels found in patients with IDDM. In view of the currently developed small molecule inhibitors of cell adhesion molecules, these independent observations together may provide a sound rationale to select P-selectin as a target for treating or preventing IDDM-associated micro- or macrovascular complications.

Download Full-text

Ileal transposition helps to regulate plasma hepatokine levels in obese Zucker (Crl:ZUC(ORL)-Leprfa) rats

Scientific Reports ◽

10.1038/s41598-021-87293-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Dominika Stygar ◽

Tomasz Sawczyn ◽

Agnieszka Dulska ◽

Elżbieta Chełmecka ◽

Łukasz Mielańczyk ◽

...

Keyword(s):

Body Weight ◽

Plasma Levels ◽

Plasma Concentrations ◽

The Body ◽

Retinol Binding Protein ◽

Fibroblast Growth Factor 21 ◽

Adult Males ◽

Total Lipids ◽

Ileal Transposition ◽

Sham Surgery

AbstractWe studied the long-term effect of ileal transposition (IT) metabolic surgery on the hepatokines: retinol-binding protein-4 (RBP4), α-2-HS-glycoprotein (aHSG/fetuin-A), and fibroblast growth factor 21 (FGF21), C-reactive protein (CRP) plasma levels, glucose metabolism, body weight, liver histology, as well as total lipids concentration in muscle, liver, and fat tissue of obese Zucker (Crl:ZUC(ORL)-Leprfa) rats. 14 adult males were randomly submitted either to IT or SHAM (control) surgery. Pre-operative hepatokines plasma levels were not significantly different in rats submitted to IT or SHAM protocol. Three months after the procedures the plasma levels of RBP4, aHSG, FGF21, and CRP were significantly lower in IT-operated animals when compared to SHAM-operated group. Three and 12 weeks after the IT and SHAM surgery, the AUCOGTT were significantly lower than AUCOGTT before the surgery. HOMA-IR was lower in rats after IT surgery in comparison to the SHAM-operated rats. Muscle and liver total lipids concentration was reduced after the IT procedure when compared to pre-IT conditions. IT had a significant reductive impact on the body weight in comparison to SHAM surgery in the 4th, 6th, 8th, and 10th week after the surgery. We conclude that IT reduces hepatokines’ plasma concentrations, muscle and liver total lipids concentration but not the inflammatory processes in the liver of Zucker (Crl:ZUC(ORL)-Leprfa) rats.

Download Full-text

Sex differences in the association of sphingolipids with age in Dutch and South-Asian Surinamese living in Amsterdam, the Netherlands

Biology of Sex Differences ◽

10.1186/s13293-020-00353-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Mirthe Muilwijk ◽

Nardie Callender ◽

Susan Goorden ◽

Frédéric M. Vaz ◽

Irene G. M. van Valkengoed

Keyword(s):

Sex Differences ◽

Waist Circumference ◽

South Asian ◽

Plasma Concentrations ◽

Plasma Lipid ◽

Ethnic Origin ◽

Sphingolipid Metabolism ◽

Cvd Risk ◽

Men And Women ◽

Liquid Chromatography Tandem Mass

Abstract Background Men have a higher risk for cardiovascular disease (CVD) early in life, while women have a higher risk later in life. The sex-related differences in CVD risk, especially by age, could be related to sphingolipid metabolism. We compared plasma sphingolipid concentrations and its increase by age in men and women. Methods Plasma concentrations of 13 types of sphingolipids were measured by liquid chromatography-tandem mass spectrometry in a random subsample of 328 men and 372 women of Dutch and South-Asian Surinamese ethnic origin, participating in the HELIUS study. Sphingolipid concentrations were compared between men and women by age group (18–39, 40–55, and 56–70 years). Multiple linear regression was used to determine sex differences in age trends in sphingolipids stratified by ethnicity. Analyses were performed without adjustment and adjusted for body mass index (BMI) and waist circumference. Results At age 18–39 years, sphingolipid concentrations were lower in women than those in men, but at age 56–70 years this was reversed. At higher age, women showed higher concentrations than men. In line, we observed a more rapid increase of sphingolipid concentrations by age in women than in men. The observed sex differences were not explained by BMI or waist circumference. Patterns of sex differences were similar across ethnic groups, although the strength of associations differed. Conclusions Mean sphingolipid concentrations increase more rapidly with age in women than in men. Therefore, plasma lipid concentrations of sphingolipids, although lower in women than in men at younger age, are higher in women than in men at older age.

Download Full-text

Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01124-7 ◽

2021 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Atsuhito Uneda ◽

Kazuhiko Kurozumi ◽

Atsushi Fujimura ◽

Kentaro Fujii ◽

Joji Ishida ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Tumor Cells ◽

In Silico ◽

Tumor Tissue ◽

The Cancer Genome Atlas ◽

Macrophage Infiltration ◽

Macrophage Migration

AbstractGlioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

Download Full-text

Personalizing Therapy for Metastatic Prostate Cancer: The Role of Solid and Liquid Tumor Biopsies

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_175510 ◽

2017 ◽

pp. 358-369 ◽

Cited By ~ 1

Author(s):

Terence W. Friedlander ◽

Colin C. Pritchard ◽

Himisha Beltran

Keyword(s):

Prostate Cancer ◽

Metastatic Prostate Cancer ◽

Tumor Tissue ◽

Neuroendocrine Differentiation ◽

Metastatic Tumor ◽

Metastatic Lesion ◽

Phenotypic Changes ◽

Tumor Biopsies ◽

Bioinformatic Approach

Although biopsies of metastatic prostate cancer are rarely undertaken in the clinical setting, there is increasing interest in developing personalized approaches to therapy by taking into account the genetic and phenotypic changes in an individual tumor. Indeed, analysis of metastatic prostate tumors can predict sensitivity to agents that inhibit DNA repair and resistance to novel hormonal agents, such as abiraterone and enzalutamide, and identify phenotypic changes, such as neuroendocrine differentiation, that have important clinical implications. Although obtaining metastatic tumor tissue is necessary for this genomic and molecular profiling, knowing when to biopsy, selecting the appropriate metastatic lesion, and interpreting the results are major challenges facing clinicians today. In this article, we discuss the rationale for obtaining metastatic tumor tissue, review the bioinformatic approach to analyzing these specimens, discuss the timing and approach to solid and liquid tumor biopsies, review the challenges associated with obtaining and acting on clinically relevant results, and discuss opportunities for the future.

Download Full-text

PD-L1 Gene Polymorphism and High Level of Plasma Soluble Pd-L1 Protein may be aSsociated with Non-Small Cell Lung Cancer

The International Journal of Biological Markers ◽

10.5301/jbm.5000170 ◽

2015 ◽

Vol 30 (4) ◽

pp. 364-368 ◽

Cited By ~ 32

Author(s):

Sensen Cheng ◽

Jinsong Zheng ◽

Jingyan Zhu ◽

Chao Xie ◽

Xia Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Plasma Levels ◽

Plasma Concentrations ◽

Small Cell ◽

Small Cell Lung ◽

High Level ◽

Nsclc Patients ◽

L1 Protein

Background PD-1 and its ligand PD-L1 belong to the co-inhibition molecules, which can downregulate immune responses. The PD-L1 polymorphism and the level of soluble PD-L1 (sPD-L1) were investigated in non-small cell lung cancer (NSCLC). Methods A total of 288 NSCLC patients and 300 controls were enrolled. An A/C polymorphism at position 8923 in the PD-L1 gene was genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. Results The prevalence of the 8923C allele was significantly higher in NSCLC patients than controls (10.2% versus 5.3%, p = 0.002, odds ratio 2.03, 95% confidence interval 1.30-3.17; data were adjusted for age and sex). NSCLC patients also showed increased plasma levels of sPD-L1 compared to controls (1.92 ng/mL versus 0.91 ng/mL, p<0.001). Furthermore, lung adenocarcinoma patients had higher sPD-L1 levels than patients with squamous cell carcinoma (p<0.01). However, no association was observed between the different genetic variants and plasma concentrations of sPD-L1. Conclusions The PD-L1 8923A/C polymorphism could be associated with increased susceptibility to NSCLC. Plasma levels of sPD-L1 are significantly increased in NSCLC patients, especially those with adenocarcinoma.

Download Full-text

Increased plasma leptin attenuates adaptive metabolism in early lactating dairy cows

Journal of Endocrinology ◽

10.1530/joe-16-0031 ◽

2016 ◽

Vol 229 (2) ◽

pp. 145-157 ◽

Cited By ~ 12

Author(s):

Richard A Ehrhardt ◽

Andreas Foskolos ◽

Sarah L Giesy ◽

Stephanie R Wesolowski ◽

Christopher S Krumm ◽

...

Keyword(s):

Dairy Cow ◽

Feed Intake ◽

Plasma Levels ◽

Plasma Concentrations ◽

Body Weight Loss ◽

Energy Output ◽

Glucose Disposal ◽

Hepatic Glycogen ◽

Metabolic Efficiency ◽

Plasma Leptin

Mammals meet the increased nutritional demands of lactation through a combination of increased feed intake and a collection of adaptations known as adaptive metabolism (e.g., glucose sparing via insulin resistance, mobilization of endogenous reserves, and increased metabolic efficiency via reduced thyroid hormones). In the modern dairy cow, adaptive metabolism predominates over increased feed intake at the onset of lactation and develops concurrently with a reduction in plasma leptin. To address the role of leptin in the adaptive metabolism of early lactation, we asked which adaptations could be countered by a constant 96-h intravenous infusion of human leptin (hLeptin) starting on day 8 of lactation. Compared to saline infusion (Control), hLeptin did not alter energy intake or milk energy output but caused a modest increase in body weight loss. hLeptin reduced plasma glucose by 9% and hepatic glycogen content by 73%, and these effects were associated with a 17% increase in glucose disposal during an insulin tolerance test. hLeptin attenuated the accumulation of triglyceride in the liver by 28% in the absence of effects on plasma levels of the anti-lipolytic hormone insulin or plasma levels of free fatty acids, a marker of lipid mobilization from adipose tissue. Finally, hLeptin increased the plasma concentrations of T4and T3by nearly 50% without affecting other neurally regulated hormones (i.e., cortisol and luteinizing hormone (LH)). Overall these data implicate the periparturient reduction in plasma leptin as one of the signals promoting conservation of glucose and energy at the onset of lactation in the energy-deficient dairy cow.

Download Full-text