Efficient therapy for refractory Pompe disease by mannose 6-phosphate analogue grafting on acid α-glucosidase.

Pompe disease is a rare disorder due to deficiency of the acid α-glucosidase (GAA) treated by enzyme replacement therapy. The present authorized treatment with rhGAA, the recombinant human enzyme, provides an important benefit in the infantile onset; however, the juvenile and adult forms of the disease corresponding to >80% of the patients are less responsive to this treatment. This resistance has been mainly attributed to an insufficiency of mannose 6-phosphate residues in rhGAA to address lysosomes through the cation-independent mannose 6-phosphate receptor (CI-M6PR).

Pharmacological modulation of LMNA SRSF1-dependent splicing abrogates diet-induced obesity in mice.

Unlabelled: Bakground/Objectives:Intense drug discovery efforts in the metabolic field highlight the need for novel strategies for the treatment of obesity. Alternative splicing (AS) and/or polyadenylation enable the LMNA gene to express distinct protein isoforms that exert opposing effects on energy metabolism and lifespan. Here we aimed to use the splicing factor SRSF1 that contribute to the production of these different isoforms as a target to uncover new anti-obesity drug.

Prevalence of otitis media with effusion in children with allergic rhinitis, a cross sectional study.

Objectives: Otitis media with effusion (OME) may be caused by various factors including Eustachian tube dysfunction, inflammatory response as well as atopy. Allergic rhinitis (AR), a common chronic disorder in children, is associated with swelling of the mucosa and can therefore result in Eustachian tube dysfunction. This study aims to compare the prevalence of OME in subjects with and without AR.

Long lasting control of viral rebound with a new drug ABX464 targeting Rev - mediated viral RNA biogenesis.

Background: Current therapies have succeeded in controlling AIDS pandemic. However, there is a continuing need for new drugs, in particular those acting through new and as yet unexplored mechanisms of action to achieve HIV infection cure. We took advantage of the unique feature of proviral genome to require both activation and inhibition of splicing of viral transcripts to develop molecules capable of achieving long lasting effect on viral replication in humanized mouse models through inhibition of Rev-mediated viral RNA biogenesis.

The role of SIOP as a platform for communication in the global response to childhood cancer.

Since the year 2000, there has been a 35% annual decrease in mortality among children under the age of five worldwide. The decrease is mainly attributed to the decrease in childhood epidemic infections, for example, due to vaccination programs. In the near future, this decrease will draw attention to paediatric non-communicable diseases (NCDs), and cancer is one of the most common.

Hope-based intervention for individuals susceptible to colorectal cancer: a pilot study.

Individuals undergoing genetic testing for hereditary colorectal cancer (HCRC) are prone to develop psychological problems. This study investigated the short-term efficacy of a hope-based intervention program in increasing hope levels and decreasing psychopathology among HCRC genetic testing recipients. A longitudinal study was carried out on HCRC genetic testing recipients recruited by the Hereditary Gastrointestinal Cancer Registry.

The mitral valve: characterisation by real-time three-dimensional transesophageal echocardiography. Current status.

The complex anatomy of mitral valve demands precise and sophisticated imaging during any intervention .Transesophageal echocardiography has been the most frequently used modality. With the advent of three-dimensional echocardiography a more comprehensive description of the mitral valve is now possible.

Evaluating different imaging strategies in children after first febrile urinary tract infection.

We conducted a retrospective multicenter review to estimate the prevalence of urological abnormalities in Chinese children with first febrile urinary tract infection (UTI) and to evaluate the selective imaging strategy recommended by the NICE guideline for detecting underlying abnormalities. Atypical UTI was defined as in the NICE UTI guideline. Overall, 576 boys and 244 girls aged below 24 months were reviewed.

Thrombotic occlusion of bilateral popliteal arteries by ball valve thrombus in left atrium.

We present a patient of mitral stenosis with a left atrial ball valve thrombus. The diagnosis was confirmed by transesophageal echocardiogram. No clot was detected in the left atrium or the left atrial appendage at surgery.

Altered expression of cell proliferation-related and interferon-stimulated genes in colon cancer cells resistant to SN38.

Irinotecan is a topoisomerase I inhibitor widely used as an anticancer agent in the treatment of metastatic colon cancer. However, its efficacy is often limited by the development of resistance. We have isolated a colon carcinoma cell line, HCT116-SN6, which displays a 6-fold higher resistance to SN38, the active metabolite of irinotecan.

Gene expression signature in advanced colorectal cancer patients select drugs and response for the use of leucovorin, fluorouracil, and irinotecan.

Purpose: In patients with advanced colorectal cancer, leucovorin, fluorouracil, and irinotecan (FOLFIRI) is considered as one of the reference first-line treatments. However, only about half of treated patients respond to this regimen, and there is no clinically useful marker that predicts response. A major clinical challenge is to identify the subset of patients who could benefit from this chemotherapy.

Impact of RNA degradation on gene expression profiles: assessment of different methods to reliably determine RNA quality.

DNA microarray technology enables investigators to measure the expression of several 1000 mRNA species simultaneously in a biological specimen. However, the reliability of the microarray technology to detect transcriptional differences representative of the original samples is affected by the quality of the extracted RNA. Thus, it is of critical importance to standardize sample-handling protocols and to perform a quality assessment of RNA preparations.

Assay for measurement of intact B-type natriuretic peptide prohormone in blood.

Background: B-Type natriuretic peptide (BNP1-32) as well as the N-terminal fragment of the prohormone containing residues 1-76 (NT-proBNP1-76), both cleavage products of the precursor proBNP1-108, are reported to be powerful markers for prognosis and risk stratification of heart failure. However, the intact precursor also circulates in the bloodstream. Assays for the detection of these cleavage products have been developed, but most of these assays may overestimate the concentrations of the cleavage products because they also measure the precursor form.

Oxaliplatin-induced mitochondrial apoptotic response of colon carcinoma cells does not require nuclear DNA.

We previously established a model of acquired oxaliplatin resistance derived from the HCT116 oxaliplatin-sensitive cell line (HCT116S) and consisting in two resistant clones (HCT116R1, HCT116R2) and their total or partial revertants (HCT116Rev1 and HCT116Rev2, respectively). Using this cellular model, we explored the contribution of mitochondrial apoptosis and nuclear DNA to oxaliplatin-mediated apoptosis induction and oxaliplatin resistance. We showed that the activity of oxaliplatin is mediated by the induction of Bax/Bak-dependent mitochondrial apoptosis and that oxaliplatin resistance is mediated by a defect in Bax/Bak activation correlating with a reduced loss of the mitochondrial transmembrane potential (DeltaPsim).

Pharmacoproteomic approach to the study of drug mode of action, toxicity, and resistance: applications in diabetes and cancer.

Proteomics is a powerful technique for investigating protein expression profiles in biological systems and their modifications in response to stimuli or to particular physiological or pathophysiological conditions. It is therefore a technique of choice for the study of drug mode of action, side-effects, toxicity and resistance. It is also a valuable approach for the discovery of new drug targets.

Insulinotropic agent ID-1101 (4-hydroxyisoleucine) activates insulin signaling in rat.

ID-1101 (4-hydroxyisoleucine), an amino acid extracted from fenugreek seeds, exhibits an interesting glucose-dependent insulin-stimulating activity. The present study was undertaken to investigate a possible extrapancreatic effect of ID-1101 on insulin signaling and action besides its previously described insulinotropic action. Insulin-sensitizing effects of ID-1101 were investigated in rat in vivo by three different approaches: 1) using euglycemic hyperinsulinemic clamps in two different rat models of insulin resistance, i.

ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan-treated metastases.

Overcoming drug resistance has become an important issue in cancer chemotherapy. Among all known mechanisms that confer resistance, active efflux of chemotherapeutic agents by proteins from the ATP-binding cassette family has been extensively reported. The aim of the present study was to determine the involvement of ABCG2 in resistance to SN38 (the active metabolite of irinotecan) in colorectal cancer.

The transcriptome of the leukemogenic homeoprotein HOXA9 in human hematopoietic cells.

Hematopoietic defects in HOXA9(-/-) mice demonstrate a key role for this homeoprotein in blood cell development. Conversely, enforced HOXA9 expression is leukemogenic in mice, and HOXA9 is frequently activated in human acute myeloid leukemia (AML). Although HOXA9 is thought to function as a transcription factor, few downstream targets have been identified.

The chemopreventive agent N-(4-hydroxyphenyl)retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the Bcl-2 family.

N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide) is a potent chemopreventive agent whose effect has been suggested to involve apoptosis induction. 4-HPR induces a loss of the mitochondrial transmembrane potential and the mitochondrial release of cytochrome c before caspase activation. Inhibition of mitochondrial membrane permeabilization (MMP) by transfection with Bcl-2 or the Cytomegalovirus UL37 gene product vMIA prevented caspase activation and cell death.