Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma.

Objective: Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC).

Methods: We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687).

Diagnostic testing approaches for the identification of patients with TRK fusion cancer prior to enrollment in clinical trials investigating larotrectinib.

Introduction: NTRK gene fusions are targetable oncogenic drivers independent of tumor type. Prevalence varies from highly recurrent in certain rare tumors to <1% in common cancers. The selective TRK inhibitor larotrectinib was shown to be highly active in adult and pediatric patients with tumors harboring NTRK gene fusions.

External qualification of the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) models for octocog alfa using real patient data.

Background: Existing adult patient pharmacokinetic (PK) data from the published Advate vs Kovaltry PK crossover study were used for this validation study. This data set is appropriate for qualification, given that it has not been previously submitted to Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) and will not have impacted the WAPPS-Hemo models for Kovaltry.

Objective: To compare the population PK parameters for Kovaltry (BAY 81-8973) derived from the WAPPS-Hemo models with PK parameters derived from noncompartmental analysis (NCA), using a validation PK dataset.

Correlation with Caries Lesion Depth of The Canary System, DIAGNOdent and ICDAS II.

Introduction: The aim of this study was to correlate lesion depth of natural caries, measured with Polarized Light Microscopy (PLM), to Canary Numbers (CN) derived from The Canary System™ (CS), numerical readings from DIAGNOdent (DD), and lesion scores from ICDAS II.

Methods: A total of 20 examination sites on extracted human molars and premolars were selected. The selected examination sites consisted of healthy and enamel caries on smooth and occlusal surfaces of each tooth.

Multi-Centre Clinical Evaluation of Photothermal Radiometry and Luminescence Correlated with International Benchmarks for Caries Detection.

Introduction: A clinical study was initiated to investigate a caries detection device (The Canary System (CS)), based on photothermal radiometry and modulated luminescence (PTR-LUM). The primary objective of this study was to determine if PTR-LUM values (in the form of Canary Numbers; CN) correlate with International Caries Diagnostic and Assessment System (ICDAS II) scores and clinical situations. The secondary objectives of this study were to monitor the safety of PTR-LUM, and collect data to determine how CN values could be used to differentiate healthy from decayed tooth surfaces on a normalized scale.

Detection of Caries Around Amalgam Restorations Using Four Different Modalities.

Objective: The aim of this study was to evaluate the ability of PTR-LUM (The Canary System, CS), laser fluorescence (DIAGNOdent, DD), LED fluorescence (Spectra), and visual inspection (ICDAS II) to detect natural decay around bonded amalgam restorations .

Methods: Seventeen extracted human molars and premolars, consisting of visually healthy (n=5) and natural cavitated (n=12) teeth were selected. For the carious teeth, caries was removed leaving some decayed tissue on the floor and or wall of the preparation.

Comparison of The Canary System and DIAGNOdent for the in vitro detection of caries under opaque dental sealants.

Aim: The aim of the present study was to investigate the ability of operators using The Canary System and DIAGNOdent to detect natural pit and fissure caries under four commonly-used opaque dental sealants.

Methods: Mixed sound and carious pits/fissures (N = 105) selected from 40 human teeth were randomly assigned (10 teeth/group) to one of four opaque sealant groups (Delton, Embrace WetBond, Helioseal F, UltraSeal XT Plus). Selected pits/fissures sites on occlusal surfaces were scanned with The Canary System and DIAGNOdent, sealed, re-scanned, and subjected to polarized light microscopy to confirm whether the scanned regions were sound or carious.

Relaxin-3 and receptors in the human and rhesus brain and reproductive tissues.

Evidence suggests that relaxin-3 may have biological functions in the reproductive and central nervous systems. To date, however, relaxin-3 biodistribution has only been investigated in the mouse, rat, pig and teleost fish. Characterizing relaxin-3 gene structure, expression patterns, and function in non-human primates and humans is critical to delineating its biological significance.

Skeletal myoblasts overexpressing relaxin improve differentiation and communication of primary murine cardiomyocyte cell cultures.

The possibility that resident myocardial progenitor cells may be re-activated by transplantation of exogenous stem cells into the post-infarcted heart has been suggested as a possible mechanism to explain the heart's functional improvement after stem cell therapy. Here we studied whether differentiation of mouse neonatal immature cardiomyocytes in vitro was influenced by mouse skeletal myoblasts C2C12, wild type or engineered to secrete the cardiotropic hormone relaxin. The cultured cardiomyocytes formed spontaneously beating clusters and temporally exhibited cardiac immunophenotypical (cKit, atrial natriuretic peptide, troponin T, connexin-43, HCN4) and electrical features (inward voltage-dependent Na(+), T- and L-type Ca(2+) currents, outward and inward K(+) currents, I(f) pacemaker current).

Functional and histopathological improvement of the post-infarcted rat heart upon myoblast cell grafting and relaxin therapy.

Although the myocardium contains progenitor cells potentially capable of regenerating tissue upon lethal ischaemic injury, their actual role in post-infarction heart healing is negligible. Therefore, transplantation of extra-cardiac stem cells is a promising therapeutic approach for post-infarction heart dysfunction. Paracrine cardiotropic factors released by the grafted cells, such as the cardiotropic hormone relaxin (RLX), may beneficially influence remodelling of recipient hearts.

Inflammation, C-reactive protein, and atherothrombosis.

Atherothrombosis of the coronary and cerebral vessels is understood to be a disorder of inflammation and innate immunity, as well as a disorder of lipid accumulation. From a vascular biology perspective, the processes of cellular adhesion, monocyte and macrophage attachment, and transmigration of immune cells across the endothelium are crucial steps in early atherogenesis and in the later stages of mature plaque rupture, particularly the transition of unstable plaque at the time of acute thrombosis. There is abundant clinical evidence demonstrating that many biomarkers of inflammation are elevated years in advance of first ever myocardial infarction (MI) or thrombotic stroke and that these same biomarkers are highly predictive of recurrent MI, recurrent stroke, diabetes, and cardiovascular death.

Paracrine effects of transplanted myoblasts and relaxin on post-infarction heart remodelling.

In the post-infarcted heart, grafting of precursor cells may partially restore heart function but the improvement is modest and the mechanisms involved remain to be elucidated. Here, we explored this issue by transplanting C2C12 myoblasts, genetically engineered to express enhanced green fluorescent protein (eGFP) or eGFP and the cardiotropic hormone relaxin (RLX) through coronary venous route to swine with experimental chronic myocardial infarction. The rationale was to deliver constant, biologically effective levels of RLX at the site of cell engraftment.

Analog of H2 relaxin exhibits antagonistic properties and impairs prostate tumor growth.

Hormone antagonists can be effective tools to delineate receptor signaling pathways and their resulting downstream physiological actions. Mutation of the receptor binding domain (RBD) of human H2 relaxin (deltaH2) impaired its biological function as measured by cAMP signaling. In a competition assay, deltaH2 exhibited antagonistic activity by blocking recombinant H2 relaxin from binding to receptors on THP-1 cells.

Relaxin enhances the oncogenic potential of human thyroid carcinoma cells.

The role of members of the insulin-like superfamily in human thyroid carcinoma is primarily unknown. Here we demonstrate the presence of RLN2 relaxin and relaxin receptor LGR7 in human papillary, follicular, and undifferentiated anaplastic thyroid carcinoma suggesting a specific involvement of relaxin-LGR7 signaling in thyroid carcinoma. Stable transfectants of the LGR7-positive human follicular thyroid carcinoma cell lines FTC-133 and FTC-238 that secrete bioactive proRLN2 revealed this hormone to act as a multifunctional endocrine factor in thyroid carcinoma cells.

Functional expression of mouse relaxin and mouse relaxin-3 in the lung from an Ebola virus glycoprotein-pseudotyped lentivirus via tracheal delivery.

The peptide hormone relaxin is a known modulator of connective tissue and the extracellular matrix by virtue of its ability to regulate matrix metalloproteinases (MMPs). Relaxin knockout mice exhibit age-related pulmonary fibrosis, and delivery of recombinant human H2 relaxin ameliorates fibrotic-like conditions in the mouse lung. We investigated whether lentiviral vectors (LVs) engineering the expression of murine relaxins could induce MMP activity in the mouse lung.

H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis.

Our study reports a preliminary investigation into the role of human H2 relaxin in prostate tumor growth. A luciferase-expressing human prostate cancer cell line, PC-3, was generated and termed PC3-Luc. PC3-Luc cells were transduced with lentiviral vectors engineering the expression of either enhanced green fluorescent protein (eGFP) or both H2 relaxin and eGFP in a bicistronic format.

Central effects of long-term relaxin expression in the rat.

A recombinant adenovirus containing the human H2 preprorelaxin (hH2) cDNA and a reporter gene was coinjected with a transactivator virus (Ad-tTA) into the lateral cerebral ventricles of female rats. Cardiovascular effects were measured over a 21-day period. Circulating vasopressin in the periphery was significantly greater (P < .

Cloning, sequencing and characterization of lentiviral-mediated expression of rhesus macaque (Macaca mulatta) interleukin-2 receptor alpha cDNA.

The rhesus macaque CD25 (RhCD25) cDNA isolated from rhesus PBMCs was found to share 95.5 and 91.9% homology with the human orthologue at the nucleotide and amino acid levels, respectively.

Relaxin-like peptides in cancer.

The members of the relaxin-like hormone family, relaxin and INSL3, also known as relaxin-like factor (RLF) or Leydig cell-derived insulin-like factor (LEY-I-L), are implicated in various mechanisms associated with tumor cell growth, differentiation, invasion and neovascularization. The recent discovery of the relaxin receptor LGR7 and the INSL3/relaxin receptor LGR8 has provided evidence of an auto/paracrine relaxin-like action in tumor tissues and enables the elucidation of the cellular pathways involved in the proposed functions of relaxin in tumor biology. Our review summarizes our current knowledge of the expression of relaxin and INSL3 in human neoplastic tissues and discusses the etiological roles of these heterodimeric peptide hormones in cancer.

Adenovirus-mediated expression of human prorelaxin promotes the invasive potential of canine mammary cancer cells.

This study reports the characterization of a recombinant adenoviral vector containing a tetracycline-regulatable promoter, driving the bicistronic expression of the human H2 preprorelaxin (hH2) cDNA and enhanced green fluorescent protein, via an internal ribosomal entry site. An hH2 ELISA was used to measure the secreted levels of recombinant hH2 in transfected canine (CF33.Mt) and human (MDA-MB-435) mammary cancer cell lines over a 6-d period; secreted peptide peaked on d 2 and 4 for the canine and human cell types, respectively.