Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies.

Bispecific antibodies and antibody fragments in various formats have been explored as a means to recruit cytolytic T cells to kill tumor cells. Encouraging clinical data have been reported with molecules such as the anti-CD19/CD3 bispecific T cell engager (BiTE) blinatumomab. However, the clinical use of many reported T cell-recruiting bispecific modalities is limited by liabilities including unfavorable pharmacokinetics, potential immunogenicity, and manufacturing challenges.

Long duration of stressful homework as a potential obesogenic factor in children: a QUALITY study.

Objective: To examine for the first time whether stressful mental tasks are associated with an unfavorable anthropometric profile in children.

Methods: A cross-sectional analysis was undertaken in 511 children. A complete anthropometric profile was assessed, and children reported their homework duration and the presence/absence of stress related to schoolwork.

DdrO is an essential protein that regulates the radiation desiccation response and the apoptotic-like cell death in the radioresistant Deinococcus radiodurans bacterium.

Deinococcus radiodurans is known for its extreme radioresistance. Comparative genomics identified a radiation-desiccation response (RDR) regulon comprising genes that are highly induced after DNA damage and containing a conserved motif (RDRM) upstream of their coding region. We demonstrated that the RDRM sequence is involved in cis-regulation of the RDR gene ddrB in vivo.

An innovative lab-based training program to help patient groups understand their disease and the research process.

Genuine partnership between patient groups and medical experts is important but challenging. Our training program meets this challenge by organizing hands-on, lab-based training sessions for members of patient groups. These sessions allow "trainees" to better understand their disease and the biomedical research process, and strengthen links between patients and local researchers.

15q11.2 microdeletion (BP1-BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: a series of 52 patients.

Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns.

In vitro and in vivo characterization of antibacterial activity and biocompatibility: a study on silver-containing phosphonate monolayers on titanium.

Infections associated with implanted medical devices are a major cause of nosocomial infections, with serious medical and economic repercussions. A variety of silver-containing coatings have been proposed to decrease the risk of infection by hindering bacterial adhesion and biofilm formation. However, the therapeutic range of silver is relatively narrow and it is important to minimize the amount of silver in the coatings, in order to keep sufficient antibacterial activity without inducing cytotoxicity.

Adrenal cortex tissue homeostasis and zonation: A WNT perspective.

The adrenal cortex plays essential roles in the control of sodium and water homeostasis, stress response, inflammation and metabolism, through secretion of glucocorticoids and mineralocorticoids. Coordinated production of these hormones relies on functional zonation of the cortex, characterised by expression of Cyp11b2 under the control of angiotensin II and plasma potassium level in zona glomerulosa (ZG) and Cyp11b1 under the control of ACTH in zona fasciculata (ZF). The mechanisms involved in the establishment of functional zonation and its maintenance during centripetal cortex cell renewal are still poorly understood.

[Pre-analytical stage for biomarker assessment in breast cancer: 2014 update of the GEFPICS' guidelines in France].

Biomarker assessment of breast cancer tumor samples is part of the routine workflow of pathology laboratories. International guidelines have recently been updated, with special regards to the pre-analytical steps that are critical for the quality of immunohistochemical and in situ hybridization procedures, whatever the biomarker analyzed. Fixation and specimen handling protocols must be standardized, validated and carefully tracked.

[2014 update of the GEFPICS' recommendations for HER2 status determination in breast cancers in France].

International guidelines on HER2 determination in breast cancer have just been updated by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), on the basis of more than ten-year practice, results of clinical trials and concordance studies. The GEFPICS group, composed of expert pathologists in breast cancer, herein presents these recommendations, adapted to the French routine practice. These guidelines highlight the possible diagnosis difficulties with regards to HER2 status determination, such as intra-tumor heterogeneity, special histological subtypes and biomarker re-evaluation during metastatic relapse.

Correlates of sedentary behaviour in 8- to 10-year-old children at elevated risk for obesity.

The purpose of this study was to describe correlates of sedentary behaviour (SED) in children at elevated risk of obesity because of parental obesity. Participants were 534 children aged 8-10 years with ≥ 1 obese parent. SED and physical activity (PA) were measured by accelerometer, screen time by self-report, and height, weight, waist circumference, and cardiovascular fitness objectively measured.

Discovery of (2S)-8-[(3R)-3-methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one: a novel potent and selective inhibitor of Vps34 for the treatment of solid tumors.

Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives.

Selective inhibition of mutant isocitrate dehydrogenase 1 (IDH1) via disruption of a metal binding network by an allosteric small molecule.

Cancer-associated point mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) confer a neomorphic enzymatic activity: the reduction of α-ketoglutarate to d-2-hydroxyglutaric acid, which is proposed to act as an oncogenic metabolite by inducing hypermethylation of histones and DNA. Although selective inhibitors of mutant IDH1 and IDH2 have been identified and are currently under investigation as potential cancer therapeutics, the mechanistic basis for their selectivity is not yet well understood. A high throughput screen for selective inhibitors of IDH1 bearing the oncogenic mutation R132H identified compound 1, a bis-imidazole phenol that inhibits d-2-hydroxyglutaric acid production in cells.

A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy.

Vps34 is a phosphoinositide 3-kinase (PI3K) class III isoform that has attracted major attention over the recent years because of its role in autophagy. Herein we describe the biological characterization of SAR405, which is a low-molecular-mass kinase inhibitor of Vps34 (KD 1.5 nM).

Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells.

Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations.

Structures of a pan-specific antagonist antibody complexed to different isoforms of TGFβ reveal structural plasticity of antibody-antigen interactions.

Various important biological pathways are modulated by TGFβ isoforms; as such they are potential targets for therapeutic intervention. Fresolimumab, also known as GC1008, is a pan-TGFβ neutralizing antibody that has been tested clinically for several indications including an ongoing trial for focal segmental glomerulosclerosis. The structure of the antigen-binding fragment of fresolimumab (GC1008 Fab) in complex with TGFβ3 has been reported previously, but the structural capacity of fresolimumab to accommodate tight interactions with TGFβ1 and TGFβ2 was insufficiently understood.

Induction of mesenchymal stem cell differentiation and cartilage formation by cross-linker-free collagen microspheres.

Because of poor self-healing ability, joint cartilage can undergo irreversible degradation in the course of various diseases or after injury. A promising approach for cartilage engineering consists of using of mesenchymal stem cells (MSC) and a differentiation factor combined with an injectable carrier biomaterial. We describe here a novel synthesis route for native collagen microspheres that does not involve the use of potentially toxic crosslinking agents.

Aerobic Fitness Indices of Children Differed Not by Body Weight Status but by Level of Engagement in Physical Activity.

Background: Moderate-to-vigorous physical activity (MVPA) improves aerobic fitness in children, which is usually assessed by maximal oxygen consumption. However, other indices of aerobic fitness have been understudied.

Objective: To compare net oxygen (VO2net), net energy consumption (Enet), net mechanical efficiency (MEnet), and lipid oxidation rate in active and inactive children across body weight statuses.

Perceived parental social support and moderate-to-vigorous physical activity in children at risk of obesity.

Purpose: Identification of factors that relate to physical activity behavior in children at higher risk for weight problems--namely, children with obese parents--is key to informing the development of effective interventions to promote physical activity and reduce obesity. The purpose of our study was to examine children's perceptions of parental social support for physical activity and the associations between these perceptions and health-enhancing physical activity behavior. Our specific objectives were to: (a) compare perceptions of parental support in children across gender and weight status; (b) compare perceptions of support across source (mother, father) and type (tangible, intangible) in normal-weight and overweight girls and boys; and (c) examine the associations between perceptions of parental support and moderate-to-vigorous physical activity (MVPA) behavior.

Implementation of ultrasonic sensing for high resolution measurement of binary gas mixture fractions.

We describe an ultrasonic instrument for continuous real-time analysis of the fractional mixture of a binary gas system. The instrument is particularly well suited to measurement of leaks of a high molecular weight gas into a system that is nominally composed of a single gas. Sensitivity < 5 × 10(-5) is demonstrated to leaks of octaflouropropane (C3F8) coolant into nitrogen during a long duration (18 month) continuous study.

Combined physical activity/sedentary behaviour associations with indices of adiposity in 8- to 10-year-old children.

Objective: Individuals may achieve high physical activity (PA) yet also be highly sedentary (SED). This study assessed adiposity in children classified by PA/SED groups.

Methods: Participants were 520 8- to 10-year-old children with ≥ 1 obese parent.

Photothermal laser microsintering of nanoporous gold.

Photothermal processing of nanoporous gold using a microfocused continuous-wave laser at a wavelength of 532 nm and a 1/e(2) spot diameter of 2.9 μm has been studied. In addition, complementary experiments have been carried out via conventional annealing.

Interaction between body weight status and walking speed in steps monitoring by GT3X accelerometer.

The measurement error of the step count function of the ActiGraph GT3X accelerometer was assessed at different walking speeds in 12 obese and 16 nonobese individuals. In comparison with visual verification, the accelerometer step count function measurement error was larger for obese individuals walking at low speeds (2.5 km·h(-1)).

The helicase HAGE prevents interferon-α-induced PML expression in ABCB5+ malignant melanoma-initiating cells by promoting the expression of SOCS1.

The tumour suppressor PML (promyelocytic leukaemia protein) regulates several cellular pathways involving cell growth, apoptosis, differentiation and senescence. PML also has an important role in the regulation of stem cell proliferation and differentiation. Here, we show the involvement of the helicase HAGE in the transcriptional repression of PML expression in ABCB5+ malignant melanoma-initiating cells (ABCB5+ MMICs), a population of cancer stem cells which are responsible for melanoma growth, progression and resistance to drug-based therapy.

Involvement of angiopoietin-like 4 in matrix remodeling during chondrogenic differentiation of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are considered for cartilage engineering given their ability to differentiate into chondrocytes. Chondrogenic differentiation of MSCs is currently triggered by micromass culture in the presence of a member of the TGF-β superfamily. However, the main constituents of the cartilaginous matrix, aggrecan and type II collagen, are degraded at the end of the differentiation process through induction of matrix metallopeptidase (MMP)13.

Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study.

Background: There is a need to develop surrogates for treatment efficacy in the neoadjuvant setting to speed-up drug development and stratify patients according to outcome. Preclinical studies showed that chemotherapy induces an antitumor immune response. In order to develop new surrogates for drug efficacy, we assessed the prognostic value of tumor-infiltrating lymphocytes (TIL) on residual disease after neoadjuvant chemotherapy (NACT) in patients with triple-negative breast cancer (TNBC).