R&D cooperation versus R&D subcontracting: empirical evidence from French survey data.

This paper uses a survey of French firms active in R&D to identify the determinants of R&D outsourcing and of the ensuing trade-off between R&D subcontracting and R&D cooperation. Internal R&D expenditures increase both the probability of outsourcing and the number of R&D partners. Investment in fundamental R&D, group belonging, and the sector’s high R&D intensity positively influences the probability of R&D outsourcing but have less impact on the number of partners. R&D subcontracting is more likely than R&D cooperation when the relationship deals with generic, standardized R&D processes, as reflected in the influence of several qualitative proxies.R&D cooperation, R&D subcontracting, organizational choices.

Stratosphere-troposphere exchange project management

The purpose is to manage the Stratosphere Troposphere Exchange Project (STEP). This includes holding and planning science team meetings, organizing sessions at conferences devoted to the results and objectives of STEP field programs, putting together special journal issues or special sections of journal issues devoted to the results of STEP, and planning and producing technical memoranda on STEP. Summary of progress and results are given

Inherent Structural Disorder and Dimerisation of Murine Norovirus NS1-2 Protein

Human noroviruses are highly infectious viruses that cause the majority of acute, non-bacterial epidemic gastroenteritis cases worldwide. The first open reading frame of the norovirus RNA genome encodes for a polyprotein that is cleaved by the viral protease into six non-structural proteins. The first non-structural protein, NS1-2, lacks any significant sequence similarity to other viral or cellular proteins and limited information is available about the function and biophysical characteristics of this protein. Bioinformatic analyses identified an inherently disordered region (residues 1–142) in the highly divergent N-terminal region of the norovirus NS1-2 protein. Expression and purification of the NS1-2 protein of Murine norovirus confirmed these predictions by identifying several features typical of an inherently disordered protein. These were a biased amino acid composition with enrichment in the disorder promoting residues serine and proline, a lack of predicted secondary structure, a hydrophilic nature, an aberrant electrophoretic migration, an increased Stokes radius similar to that predicted for a protein from the pre-molten globule family, a high sensitivity to thermolysin proteolysis and a circular dichroism spectrum typical of an inherently disordered protein. The purification of the NS1-2 protein also identified the presence of an NS1-2 dimer in Escherichia coli and transfected HEK293T cells. Inherent disorder provides significant advantages including structural flexibility and the ability to bind to numerous targets allowing a single protein to have multiple functions. These advantages combined with the potential functional advantages of multimerisation suggest a multi-functional role for the NS1-2 protein

R&D cooperation versus R&D subcontracting: empirical evidence from French survey data

This paper uses a survey of French firms active in R&D to identify the determinants of the trade-off between R&D subcontracting and R&D cooperation. We observe that R&D subcontracting is more likely than R&D cooperation when the partner is chosen on objective criteria, such as prices, quality certificates and geographic proximity. Subcontracting relationships also involve less uncertainty, are less likely to lead to patent deposits and less frequently involve public research institutions. These results are coherent with the hypothesis that R&D subcontracting mainly concerns standardized R&D processes.R&D cooperation, R&D subcontracting, organizational choices,

Postpartum cardiac arrest in a woman with an uncorrected sinus venosus type of atrial septal defect: A case report

The number of women with congenital heart disease (CHD) surviving to childbearing age is continuously growing. Although most pregnancies in this patient-population are well tolerated, there is a significant risk of potentially fatal complications. We describe a case of a previously completely asymptomatic patient who was diagnosed late during pregnancy with an inferior sinus venosus type atrial septal defect (ISV-ASD) and anomalous connection of all right pulmonary veins (PAPVC) who presented a cardiac arrest with ventricular fibrillation the day after delivery. She recovered completely and underwent subsequent surgical repair and implantation of a subcutaneous defibrillator (S-ICD)

Identification of N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1,2 and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies

Pan Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2 and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model and pre-clinical profile of the potent and selective pan PIM kinase inhibitor 8 (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor 1, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, 8 entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies

Identification of <i>N</i>‑(4-((1<i>R</i>,3<i>S</i>,5<i>S</i>)‑3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2, and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies

Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model, and preclinical profile of the potent and selective pan PIM kinase inhibitor compound <b>8</b> (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor compound <b>3</b>, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, compound <b>8</b> entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies

Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive malignancy that is characterized by poor prognosis. Large-scale pharmacological profiling across more than 100 hematological cell line models identified a subset of MCL cell lines that are highly sensitive to the B cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin. Sensitive MCL models exhibited chronic activation of the BCR-driven classical nuclear factor-{kappa}B (NF-{kappa}B) pathway, whereas insensitive cell lines displayed activation of the alternative NF-{kappa}B pathway. Transcriptome sequencing revealed genetic lesions in alternative NF-{kappa}B pathway signaling components in ibrutinib-insensitive cell lines, and sequencing of 165 samples from patients with MCL identified recurrent mutations in TRAF2 or BIRC3 in 15% of these individuals. Although they are associated with insensitivity to ibrutinib, lesions in the alternative NF-{kappa}B pathway conferred dependence on the protein kinase NIK (also called mitogen-activated protein 3 kinase 14 or MAP3K14) both in vitro and in vivo. Thus, NIK is a new therapeutic target for MCL treatment, particularly for lymphomas that are refractory to BCR pathway inhibitors. Our findings reveal a pattern of mutually exclusive activation of the BCR-NF-{kappa}B or NIK-NF-{kappa}B pathways in MCL and provide critical insights into patient stratification strategies for NF-{kappa}B pathway-targeted agents