Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy.

We designed and synthesized a new series of fatty acid synthase (FASN) inhibitors with potential utility for the treatment of cancer. Extensive SAR studies led to highly active FASN inhibitors with good cellular activity and oral bioavailability, exemplified by compound 34. Compound 34 is a potent inhibitor of human FASN (IC = 28 nM) that effectively inhibits proliferation of A2780 ovarian cells (IC = 13 nM) in lipid-reduced serum (LRS).

Selective inhibition of intestinal guanosine 3',5'-cyclic monophosphate signaling by small-molecule protein kinase inhibitors.

The guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase II (cGKII) serine/threonine kinase relays signaling through guanylyl cyclase C (GCC) to control intestinal fluid homeostasis. Here, we report the discovery of small-molecule inhibitors of cGKII. These inhibitors were imidazole-aminopyrimidines, which blocked recombinant human cGKII at submicromolar concentrations but exhibited comparatively little activity toward the phylogenetically related protein kinases cGKI and cAMP-dependent protein kinase (PKA).

Cancer cells differentially activate and thrive on de novo lipid synthesis pathways in a low-lipid environment.

Increased lipogenesis is a hallmark of a wide variety of cancers and is under intense investigation as potential antineoplastic target. Although brisk lipogenesis is observed in the presence of exogenous lipids, evidence is mounting that these lipids may adversely affect the efficacy of inhibitors of lipogenic pathways. Therefore, to fully exploit the therapeutic potential of lipid synthesis inhibitors, a better understanding of the interrelationship between de novo lipid synthesis and exogenous lipids and their respective role in cancer cell proliferation and therapeutic response to lipogenesis inhibitors is of critical importance.

Atypical plasma lipid profile in cancer patients: cause or consequence?

The aberrant blood lipoprotein levels in cancer patients are reported to be associated with cancer risk and mortality incidents however, there are several discrepancies in the previous reports. Hence the clinical usefulness of plasma/serum levels in risk stratification of a variety of cancers remains elusive. The present review highlights and compiles findings from different research groups regarding association of plasma lipoprotein levels with the risk of developing various types of cancer.

Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids.

One of the most important metabolic hallmarks of cancer cells is enhanced lipogenesis. Depending on the tumor type, tumor cells synthesize up to 95% of saturated and mono-unsaturated fatty acids (FA) de novo in spite of sufficient dietary lipid supply. This lipogenic conversion starts early when cells become cancerous and further expands as the tumor cells become more malignant.

ATP-citrate lyase: a key player in cancer metabolism.

ATP-citrate lyase (ACLY) is a cytosolic enzyme that catalyzes the generation of acetyl CoA from citrate. Acetyl CoA is a vital building block for the endogenous biosynthesis of fatty acids and cholesterol and is involved in isoprenoid-based protein modifications. Acetyl CoA is also required for acetylation reactions that modify proteins, such as histone acetylation.

ATP citrate lyase knockdown induces growth arrest and apoptosis through different cell- and environment-dependent mechanisms.

ATP citrate lyase (ACLY) is a cytosolic enzyme that catalyzes generation of acetyl-CoA, which is a vital building block for fatty acid, cholesterol, and isoprenoid biosynthesis. ACLY is upregulated in several types of cancer, and its inhibition induces proliferation arrest in certain cancer cells. As ACLY is involved in several pathways, its downregulation may affect multiple processes.

ATP-citrate lyase: a mini-review.

ATP-citrate lyase (ACLY) is a cytosolic enzyme that catalyzes generation of acetyl-CoA from citrate. Acetyl-CoA is a vital building block for the endogenous biosynthesis of fatty acids and cholesterol and is involved in isoprenoid-based protein modifications. Acetyl-CoA is also required for acetylation reactions that modify proteins such as histone acetylation.

De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation.

Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry-based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors.

Validation of an image simulation technique for two computed radiography systems: an application to neonatal imaging.

Purpose: The purpose of this study is to develop a computer model to simulate the image acquisition for two computed radiography (CR) imaging systems used for neonatal chest imaging: (1) The Agfa ADC Compact, a flying spot reader with powder phosphor image plates (MD 40.0); and (2) the Agfa DX-S, a line-scanning CR reader with needle crystal phosphor image plates (HD 5.0).

Simulation of image detectors in radiology for determination of scatter-to-primary ratios using Monte Carlo radiation transport code MCNP/MCNPX.

Purpose: The purpose of this study was to compare and validate three methods to simulate radiographic image detectors with the Monte Carlo software MCNP/MCNPX in a time efficient way.

Methods: The first detector model was the standard semideterministic radiography tally, which has been used in previous image simulation studies. Next to the radiography tally two alternative stochastic detector models were developed: A perfect energy integrating detector and a detector based on the energy absorbed in the detector material.

Cu filtration for dose reduction in neonatal chest imaging.

As neonatal chest images are frequently acquired to investigate the life-threatening lung diseases in prematurely born children, their optimisation in terms of X-ray exposure is required. The aim of this study was to investigate whether such dose-optimisation studies could be performed using a Monte Carlo computer model. More specifically, a Monte Carlo computer model was used to investigate the influence of Cu filtration on image quality and dose in neonatal chest imaging.

Effective dose analysis of three-dimensional rotational angiography during catheter ablation procedures.

There is increasing use of three-dimensional rotational angiography (3DRA) during cardiac ablation procedures. As compared with 2D angiography, a large series of images are acquired, creating the potential for high radiation doses. The aim of the present study was to quantify patient-specific effective doses.

Experimental validation of Monte Carlo calculations with a voxelized Rando-Alderson phantom: a study on influence parameters.

The development and improvement of techniques for an accurate dose assessment in medical physics is an important task. In this study, we focus on the validation of Monte Carlo calculations, by comparing organ doses assessed experimentally with thermoluminescent detectors in the Rando-Alderson phantom with doses calculated for a voxelized model of the same phantom for some typical x-ray procedures. A detailed study has been performed to identify the key parameters that affect the determination of organ doses.

Patient dose in neonatal units.

Lung disease represents one of the most life-threatening conditions in prematurely born children. In the evaluation of the neonatal chest, the primary and most important diagnostic study is therefore the chest radiograph. Since prematurely born children are very sensitive to radiation, those radiographs may lead to a significant radiation detriment.

Calculation of organ doses in x-ray examinations of premature babies.

Lung disease represents one of the most life-threatening conditions in prematurely born children. In the evaluation of the neonatal chest, the primary and most important diagnostic study is the chest radiograph. Since prematurely born children are very sensitive to radiation, those radiographs may lead to a significant radiation detriment.

A study of the correlation between dose area product and effective dose in vascular radiology.

The purpose of the multi-centre study was to assess dose area product (DAP) and effective dose of patients undergoing angiography of the lower limbs in Belgium and to investigate the correlation between DAP and effective dose. DAP values were measured in 12 centres and compared with the national diagnostic reference levels (DRLs). The effective dose (E) was estimated by multiplying the DAP with case-specific conversion coefficients (CCs) that were calculated with Monte Carlo software MCNP5.

Results of a European survey on patient doses in paediatric radiology.

Paediatric patients represent a very specific group within the radiology department. Compared to adult patients, they are more sensitive to radiation. As they are sometimes submitted to several radiology procedures, dose and image quality should be well balanced.

Radiation dose survey in a paediatric cardiac catheterisation laboratory equipped with flat-panel detectors.

Flat-panel X-ray detectors for fluoroscopy represent a modern imaging equipment that is being implemented in paediatric cardiac catheterisation laboratories. Infants and children represent a group of patients with a high radiosensitivity. A survey of 273 (126 diagnostic and 147 therapeutic) paediatric catheterisations was performed to investigate the radiation doses delivered by the new X-ray system.

Diagnostic reference levels in angiography and interventional radiology: a Belgian multi-centre study.

The purpose of this study was to determine diagnostic reference levels (DRLs) for common angiographic and interventional procedures in Belgium. Dose Area Product (DAP) measurements were performed on 21 systems, (13 angiography and 4 vascular surgery centres). Type of procedure, total DAP, patient weight and height were collected on a daily basis during 1 y.

Image quality assessment using the CD-DISC phantom for vascular radiology and vascular surgery.

The purpose of the study was to evaluate image quality (IQ) associated with vascular radiology and vascular surgery procedures in Belgium and to determine reference values for future image quality assessment. IQ was evaluated with the CD-DISC contrast-detail phantom. This circular PMMA phantom contains 225 holes with different diameter and depth, to quantify resolution and contrast.

Downregulation of two novel genes in Sl/Sld and W(LacZ)/Wv mouse jejunum.

Interstitial cells of Cajal (ICC) are the so-called pacemaker cells of the gut. W(LacZ)/Wv and Sl/Sld mice lack ICC surrounding the myenteric plexus (MP) in the jejunum. We compared the gene expression profile of wild type (WT) and W(LacZ)/Wv and Sl/Sld mice using suppression subtractive hybridization (SSH), generating a cDNA library of 1303 clones from which 48 unique sequences were differentially expressed with Southern blot.

Towards a proposition of a diagnostic (dose) reference level for mammographic acquisitions in breast screening measurements in Belgium.

A diagnostic reference level (DRL) is a dose level for a typical X-ray examination of a group of patients with standard body sizes and for broadly defined types of equipment. These levels are expected not to be exceeded for standard procedures when good and normal practice regarding diagnostic and technical performance is applied. In this paper, we have calculated DRLs for screening mammography in Belgium.

Subtractive hybridization unravels a role for the ion cotransporter NKCC1 in the murine intestinal pacemaker.

In the small intestine, interstitial cells of Cajal (ICC) surrounding the myenteric plexus generate the pacemaking slow waves that are essential for an efficient intestinal transit. The underlying molecular mechanisms of the slow wave are poorly known. Our aim was to identify ICC-specific genes and their function in the mouse jejunum.

WZsGreen/+: a new green fluorescent protein knock-in mouse model for the study of KIT-expressing cells in gut and cerebellum.

In the small intestine, interstitial cells of Cajal (ICC) surrounding the myenteric plexus generate the pacemaking slow waves that are essential for an efficient intestinal transit. The underlying molecular mechanisms of the slow wave are poorly known. KIT is currently the sole practical marker for ICC.