Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer.

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions.

A prospective, multicenter, observational study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in Japan.

Real-world studies permit inclusion of a more diverse patient population and provide more information on the effectiveness of treatments used in routine clinical practice. This prospective, multicenter, observational study investigated the effectiveness and safety of ixazomib plus lenalidomide and dexamethasone (IRd) in 295 patients with relapsed/refractory multiple myeloma (RRMM) in routine clinical practice in Japan. Patients had a median age of 74 years, 80.

Efficacy and Safety of Ixazomib Plus Lenalidomide and Dexamethasone Following Injectable PI-Based Therapy in Relapsed/Refractory Multiple Myeloma.

This nationwide, multicenter, open-label, single-arm study evaluated the efficacy and safety of the oral proteasome inhibitor (PI), ixazomib plus lenalidomide (LEN) and dexamethasone (DEX) (IRd) following injectable PI-based therapy for relapsed/refractory multiple myeloma (RRMM). Of 45 patients enrolled, 36 patients received IRd after achieving at least a minor response to 3 cycles of bortezomib or carfilzomib plus LEN + DEX (VRd, n=6; KRd, n=30). At median follow-up of 20.

Characterization of Fasiglifam-Related Liver Toxicity in Dogs.

Fasiglifam, a potent and highly selective agonist of G protein-coupled receptor 40, was developed for the treatment of type 2 diabetes mellitus. However, phase III clinical programs were terminated owing to liver safety concerns. Fasiglifam-related liver toxicity was also observed in repeat-dose dog toxicology studies, characterized by granulomatous inflammation with crystal formation in the liver and/or bile ducts.

Biologic Response of Colorectal Cancer Xenograft Tumors to Sequential Treatment with Panitumumab and Bevacizumab.

Recent studies in RAS wild-type (WT) metastatic colorectal cancer (mCRC) suggest that the survival benefits of therapy using anti-epidermal growth factor receptor (anti-EGFR) and anti-vascular endothelial growth factor (anti-VEGF) antibodies combined with chemotherapy are maximized when the anti-EGFR antibody is given as first-line, followed by subsequent anti-VEGF antibody therapy. We report reverse-translational research using LIM1215 xenografts of RAS WT mCRC to elucidate the biologic mechanisms underlying this clinical observation. Sequential administration of panitumumab then bevacizumab (PB) demonstrated a stronger tendency to inhibit tumor growth than bevacizumab then panitumumab (BP).

Evaluation of drug effects on cerebral blood flow and glucose uptake in un-anesthetized and un-stimulated rats: application of free-moving apparatus enabling to keep rats free during PET/SPECT tracer injection and uptake.

Objectives: The purpose of this study is the development of novel fluorine-18-fluorodeoxyglucose (F-FDG)-PET and Tc-hexamethylpropylene amine oxime (HMPAO) SPECT methods with free-moving apparatus on conscious rats to investigate brain activity without the effects of anesthesia and tactual stimulation. We also assessed the sensitivity of the experimental system by an intervention study using fluoxetine as a reference drug.

Materials And Methods: A catheter was inserted into the femoral vein and connected to a free-moving cannula system.

Glucose uptake of the muscle and adipose tissues in diabetes and obesity disease models: evaluation of insulin and β3-adrenergic receptor agonist effects by F-FDG.

Objective: One of the major causes of diabetes and obesity is abnormality in glucose metabolism and glucose uptake in the muscle and adipose tissue based on an insufficient action of insulin. Therefore, many of the drug discovery programs are based on the concept of stimulating glucose uptake in these tissues. Improvement of glucose metabolism has been assessed based on blood parameters, but these merely reflect the systemic reaction to the drug administered.

Biomarker discovery for drug-induced phospholipidosis: phenylacetylglycine to hippuric acid ratio in urine and plasma as potential markers.

Context: Drug-induced phospholipidosis is one of the significant concerns in drug development, especially in safety assessment and noninvasive diagnostic tool is highly desirable.

Objective: The objective of this study is to explored novel biomarkers for phospholipidosis using a metabolomic approach.

Method: NMR spectrometry and LC/MS/MS analyses were applied to urine and plasma of rats administrated cationic amphiphilic drugs.

Method development and validation for simultaneous quantitation of endogenous hippuric acid and phenylacetylglycine in rat urine using liquid chromatography coupled with electrospray ionization tandem mass spectrometry.

Urinary hippuric acid (HA) and phenylacetylglycine (PAG) are biomarker candidates for drug-induced phospholipidosis (PLD). To confirm their utility in preclinical and clinical settings, it is essential to develop and validate their quantification method in advance. In this study, we have applied liquid chromatography-tandem mass spectrometry (LC/MS/MS) for simultaneous quantification of HA and PAG in rat urine, and matrix based ion suppression was assessed by post-column infusion assay.

Evaluation of the therapeutic efficacy of a MEK inhibitor (TAK-733) using ¹⁸F-fluorodeoxyglucose-positron emission tomography in the human lung xenograft model A549.

Objective: The aim of this study was to evaluate the potential of (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) for monitoring the therapeutic efficacy of TAK-733, an inhibitor of mitogen-activated protein kinase kinase, in nude rats bearing A549 (human lung carcinoma) xenografts.

Methods: TAK-733 was administered orally by gavage to nude xenograft rats for 2 weeks, at dosage levels of 0 (0.5% w/v methylcellulose solution), 1, 3, and 10 mg/kg/day (n = 8/dose).

18F-FDG PET and intravascular ultrasonography (IVUS) images compared with histology of atherosclerotic plaques: 18F-FDG accumulates in foamy macrophages.

Purpose: Intravascular ultrasonography (IVUS) and (18)F-FDG PET have been used to evaluate the efficacy of antiatherosclerosis drugs. These two modalities image different characteristics of atherosclerotic plaques, and a comparison of IVUS and PET images with histology has not been performed. The aim of this study was to align IVUS and PET images using anatomic landmarks in Watanabe heritable hyperlipidaemic (WHHL) rabbits, enabling comparison of their depiction of aortic atherosclerosis.

Comparison of contrast agents for atherosclerosis imaging using cultured macrophages: FDG versus ultrasmall superparamagnetic iron oxide.

Unlabelled: Various noninvasive imaging methods have been developed to evaluate atherosclerotic plaques. Among them, (18)F-FDG PET and MR imaging with ultrasmall superparamagnetic iron oxide particles (USPIO) have been used to quantify plaque inflammation. Both methods are based on the efficient uptake of FDG and USPIO by macrophages in atherosclerotic lesions.

Ultrasonography for ureteral stone detection in patients with or without caliceal dilatation.

Purpose: To evaluate the relationship between the degree of hydronephrosis and the detection rates of ureteral stones with ultrasonography (US).

Methods: Of 250 consecutive patients with suspected ureterolithiasis, 214 who were diagnosed with ureterolithiasis were enrolled in this study. First, both kidneys were observed by US to evaluate the intrarenal collecting systems.

Oral low-dose dexamethasone for androgen-independent prostate cancer patients.

We retrospectively evaluated the outcome of oral low-dose dexamethasone (DXM) therapy for androgen-independent prostate cancer (AIPC). Between January 1999 and April 2006, 99 consecutive patients with AIPC were enrolled in this study. The median patient age was 70 years (range 46-86), and the median pretreatment prostate-specific antigen (PSA) level was 243 ng/ml (range 8.

Relationship between in vitro phospholipidosis assay using HepG2 cells and 2-week toxicity studies in rats.

Drug candidates under development by industry frequently show phospholipidosis as a side-effect in pre-clinical toxicity studies. This study sets up a cell-based assay for drug-induced phospholipidosis (PLD) and its performance was evaluated based on the in vivo PLD potential of compounds in 2-week toxicity studies in rats. When HepG2 cells were exposed simultaneously to PLD-inducing chemicals and a phospholipid having a fluorophore, an accumulation of phospholipids was detected as an increasing fluorescent intensity.

Clinical effect of alpha 1D/A adrenoceptor inhibitor naftopidil on benign prostatic hyperplasia: an international prostate symptom score and King's Health Questionnaire assessment.

Objectives: To examine the effect of alpha 1D/A adrenoceptor inhibitor naftopidil on health-related quality of life (QOL) in men with benign prostatic hyperplasia (BPH).

Methods: A total of 56 newly diagnosed patients with symptomatic BPH were prospectively enrolled and treated with 50 mg naftopidil daily for more than 12 weeks. All underwent pre-treatment documentation of lower urinary tract symptoms, QOL assessment using the international prostate symptom score (IPSS) and King's Health Questionnaire (KHQ), and uroflowmetry.

Transgenic rats overexpressing the human MrgX3 gene show cataracts and an abnormal skin phenotype.

The human MrgX3 gene, belonging to the mrgs/SNSRs (mas related genes/sensory neuron specific receptors) family, was overexpressed in transgenic rats using the actin promoter. Two animal lines showed cataracts with liquification/degeneration and swelling of the lens fiber cells. The transient epidermal desquamation was observed in line with higher gene expression.

Characterization of transgenic rats constitutively expressing vitamin D-24-hydroxylase gene.

Vitamin D-24-hydroxylase (CYP24) is one of the enzymes responsible for vitamin D metabolism. CYP24 catalyzes the conversion of 25-hydroxyvitamin D(3) [25(OH)D(3)] to 24,25-dihydroxyvitamin D(3) [24,25(OH)(2)D(3)] in the kidney. CYP24 is also involved in the breakdown of 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the active form of vitamin D(3).