Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers.

The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens. Despite advances in treatment with immune checkpoint inhibitors, there is an unmet need in the treatment of MSI cancers. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy.

Design, Synthesis, and In Vitro and In Vivo Evaluation of Cereblon Binding Bruton's Tyrosine Kinase (BTK) Degrader CD79b Targeted Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) are an established modality that allow for targeted delivery of a potent molecule, or payload, to a desired site of action. ADCs, wherein the payload is a targeted protein degrader, are an emerging area in the field. Herein we describe our efforts of delivering a Bruton's tyrosine kinase (BTK) bifunctional degrader via a CD79b mAb (monoclonal antibody) where the degrader is linked at the ligase binding portion of the payload via a cleavable linker to the mAb.

Continuous low-dose infusion of patupilone increases the therapeutic index in mouse and rat tumour models.

Patupilone is a microtubule-targeted cytotoxic agent with clinical efficacy, but causes diarrhoea in more than 80% of patients. The efficacy and tolerability of patupilone delivered continuously by subcutaneous (s.c.

Continuous low plasma concentrations of everolimus provides equivalent efficacy to oral daily dosing in mouse xenograft models of human cancer.

Purpose: Everolimus is a drug used successfully in a number of different oncology indications, but significant on-target toxicities exist. We explored the possibility of improving the therapeutic index (TI) by studying alternative means of administering the drug based upon low continuous dosing.

Methods: All studies were performed using naïve nude mice or nude mice bearing s.

Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations.

The pan-phosphoinositide 3-kinase (PI3K) inhibitor BKM120 was found, at high concentrations, to cause cell death in various cellular systems, irrespective of their level of PI3K addiction. Transcriptional and biochemical profiling studies were used to identify the origin of these unexpected and apparently PI3K-independent effects. At 5- to 10-fold, the concentration needed to half-maximally inhibit PI3K signaling.

Determinants of 6-month maternal satisfaction with breastfeeding experience in a multicenter prospective cohort study.

Although a personally defined experience, successful breastfeeding is usually measured with regard to duration. This study investigated the determinants of maternal satisfaction with breastfeeding experience for 907 mothers enrolled in a prospective cohort study. Despite a median breastfeeding duration (18 weeks) that fell short of recommendations, 822 mothers (90.

CD-ROM-based program for breastfeeding mothers.

The vast majority of breastfeeding mothers in Western countries have routine access to multimedia and Internet resources at home. The aim of this study was to assess the effectiveness of a CD-ROM-based intervention in increasing the rates of breastfeeding. We conducted a pre- and post-intervention study involving four control and four intervention maternity units in France.

Requesting physicians' experiences regarding infectious disease consultations.

Background: Solicited consultations constitute a substantial workload for infectious disease (ID) specialists in the hospital setting. The objectives of this survey were to describe requesting physicians' experiences regarding ID consultations.

Methods: A cross-sectional survey was conducted in a university-affiliated hospital in France in 2009.

Identification of novel genes potentially involved in somatic embryogenesis in chicory (Cichorium intybus L.).

Background: In our laboratory we use cultured chicory (Cichorium intybus) explants as a model to investigate cell reactivation and somatic embryogenesis and have produced 2 chicory genotypes (K59, C15) sharing a similar genetic background. K59 is a responsive genotype (embryogenic) capable of undergoing complete cell reactivation i.e.

[Developing patient information sheets in general practice. Proposal for a methodology].

Background: Health information is patients' wish and right. For general practitioners, it is a duty, a legal obligation and a pre-requisite in any preventive approach. Written information must complete oral information since it improves health care quality.

Breastfeeding outcomes for mothers with and without home access to e-technologies.

Aim: To estimate the percentage of breastfeeding mothers with home access to e-technologies and to compare breastfeeding outcomes for mothers with and without access to e-technologies.

Methods: We conducted a prospective observational study of 550 breastfeeding mothers discharged from nine maternity units in France.

Results: Overall, 435 mothers (79%; 95% confidence interval [95% CI], 75-82) had home access to e-technologies.