Search results for "MODIFIERS"

Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

2018

Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5′ splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformati…

Cohen Syndrome-Associated Cataract Is Explained by VPS13B Functions in Lens Homeostasis and Is Modified by Additional Genetic Factors

2020

International audience; Purpose: Cohen syndrome (CS) is a rare genetic disorder caused by variants of the VPS13B gene. CS patients are affected with a severe form of retinal dystrophy, and in several cases cataracts also develop. The purpose of this study was to investigate the mechanisms and risk factors for cataract in CS, as well as to report on cataract surgeries in CS patients.Methods: To understand how VPS13B is associated with visual impairments in CS, we generated the Vps13b∆Ex3/∆Ex3 mouse model. Mice from 1 to 3 months of age were followed by ophthalmoscopy and slit-lamp examinations. Phenotypes were investigated by histology, immunohistochemistry, and western blot. Literature anal…

Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

2021

Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions th…

VALUTAZIONE DELL' EFFICACIA DI DERIVATI ANFIFILICI DEL PEG COME " SURFACE MODIFIERS" DI NANOCARRIER DI FARMACI

2011

Usefulness of abdominal ultrasonography in the analysis of endoscopic activity in patients with Crohn's disease: changes following treatment with imm…

2013

The objective of this study was to analyze the accuracy of abdominal ultrasonography (AUS) in the assessment of mucosal healing in patients with Crohn's disease (CD) receiving immunomodulators and/or biological treatment, with ileocolonoscopy as the reference standard.Thirty patients were included in a prospective longitudinal study. All patients underwent ileocolonoscopy and AUS before and after a minimum of one year of treatment. The Crohn's Disease Endoscopic Inflammatory Index of Severity (CDEIS) was used for endoscopic assessment whereas AUS was analyzed by means of bowel wall thickness, color Doppler grade and percentage of increase of parietal enhancement after contrast injection.In …

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

2014

Introduction More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen re…

Thymosin α1 and α-Inteferon with Cisplatin and Etoposide in Advanced Non-Small-Cell Lung Cancer: A Phase II Study

1993

In recent years, biological response modifiers (BRMs) have emerged as an important new class of agents for treating cancer. Agents such as interferon (IFN) and interleukin 2 (IL-2) have been reported to induce significant tumor regression in various types of cancer usually resistant to chemotherapy (1,12), but their use in non-small-cell lung cancer (NSCLC) has received little attention.

P228 Cytomegalovirus Infection: is it a cause of flare-up in inflammatory bowel diseases?

2020

Abstract Background The presence of CMV in blood is quite common in patients with severe flares of ulcerative colitis (UC) and Crohn’s disease (CD) and seems to predict an adverse outcome. The impact of antiviral treatment on CMV in this setting (indications and drug options) is an unresolved issue. Our aim was to reassess the CMV role in patients with IBD hospitalised for severe exacerbations, analysing the relationship between CMV positivity, clinical characteristics, antiviral therapy and disease outcomes. Methods We evaluated a homogeneous cohort of 97 consecutive patients with IBD hospitalised from 2012 to 2018. Data regarding age, gender, smoke, familial predisposition, type of IBD, e…

Cytokines with Possible Clinical Utility

1987

Biological response modifiers (BRM) are agents aimed at reducing tumor growth, not primarily by exerting direct cytotoxic effects but by modulation of tumor gene expression (e.g., induction of differentiation) or by enhancing host defense mechanisms directed against cancer cells. BRM as primary therapy or as adjuncts to cytotoxic agents in the treatment of cancers have attracted increasing interest in view of stagnating clinical results in many areas [1], and there is increasing evidence of in vitro and in vivo efficacy of these agents. Furthermore, advances in molecular biology suggesting that oncogenes and their products play a crucial role in oncogenesis support approaches to modulation …

Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA

2017

There is a renewed interest from the pharmaceutical field to develop oral formulations of compounds, such as peptides, oligonucleotides, and polar drugs. However, these often suffer from insufficient absorption across the intestinal mucosal barrier. One approach to circumvent this problem is the use of absorption modifying excipient(s) (AME). This study determined the absorption enhancing effect of four AMEs (sodium dodecyl sulfate, caprate, chitosan, N-acetylcysteine) on five model compounds in a rat jejunal perfusion model. The aim was to correlate the model compound absorption to the blood-to-lumen clearance of the mucosal marker for barrier integrity, 51Cr-EDTA. Sodium dodecyl sulfate a…