Patient-reported outcomes predict survival and adverse events following anticancer treatment initiation in advanced HER2-positive breast cancer.

BACKGROUND: The prognostic value of patient-reported outcomes (PROs) has been minimally explored in advanced breast cancer (BC), and their comparative prognostic performance against Eastern Cooperative Oncology Group performance status (ECOG PS) is largely unknown. PATIENTS AND METHODS: This study pooled individual participant data from clinical trials CLEOPATRA, EMILIA, and MARIANNE. Pre-treatment PRO associations with overall survival (OS), progression-free survival (PFS), and grade ≥3 adverse events were evaluated via Cox proportional hazards regression. Prognostic performance was assessed with the C-statistic (c). PRO values were collected via the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. All analyses were stratified by study and treatment arms. Analyses adjusted for known prognostic variables were conducted. Exploratory analysis of the prognostic performance of PROs compared to ECOG PS was undertaken. RESULTS: The study included data from 2894 patients initiated on contemporary therapies including pertuzumab (n = 765), trastuzumab (n = 1173), trastuzumab emtansine (n = 1225), taxanes (n = 1173), lapatinib (n = 496), and capecitabine (n = 496). On univariable and adjusted analysis, patient-reported physical well-being, functional well-being, and BC subscale were all identified to be associated with OS, PFS, and grade ≥3 adverse events (P < 0.05). Patient-reported physical well-being was the most prognostic PRO for all assessed outcomes. The OS prognostic performance of physical well-being (c = 0.58) was superior to ECOG PS (c = 0.56) (P < 0.05), with multivariable analysis indicating that both provide independent information (P < 0.0001). CONCLUSIONS: PROs were identified as independent prognostic factors for OS, PFS, and grade ≥3 adverse events in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced BC initiating contemporary treatment options. Further, patient-reported physical well-being was more prognostic of OS than ECOG PS and contained independent information. PROs have value as prognostic and stratification factors for clinical use and research trials of anticancer treatment in HER2-positive ABC.

Constitutive JunB expression, associated with the JAK2 V617F mutation, stimulates proliferation of the erythroid lineage.

The JAK2 V617F mutation, present in the majority of polycythemia vera (PV) patients, causes constitutive activation of JAK2 and seems to be responsible for the PV phenotype. However, the transcriptional changes triggered by the mutation have not yet been totally characterized. In this study, we performed a large-scale gene expression study using serial analysis of gene expression in bone marrow cells of a newly diagnosed PV patient harboring the JAK2 V617F mutation and in normal bone marrow cells of healthy donors. JUNB was one of the genes upregulated in PV, and we confirmed, by quantitative real-time PCR, an overexpression of JUNB in hematopoietic cells of other JAK2 V617F PV patients. Using Ba/F3-EPOR cell lines and primary human erythroblast cultures, we found that JUNB was transcriptionally induced after erythropoietin addition and that JAK2 V617F constitutively induced JunB protein expression. Furthermore, JUNB knockdown reduced not only the growth of Ba/F3 cells by inducing apoptosis, but also the clonogenic and proliferative potential of human erythroid progenitors. These results establish a role for JunB in normal erythropoiesis and indicate that JunB may play a major role in the development of JAK2 V617F myeloproliferative disorders.

Molecular analysis of a major locus for resistance to downy mildew in sunflower with specific PCR-based markers.

Resistance of sunflower to the obligate parasite Plasmopara halstedii is conferred by specific dominant genes, denoted Pl. The Pl6 locus confers resistance to all races of P. halstedii except one, and must contain at least 11 tightly linked genes each giving resistance to different downy mildew races. Specific primers were designed and used to amplify 13 markers covering a genetic distance of about 3 cM centred on the Pl6 locus. Cloning and sequence analysis of these 13 markers indicate that Pl6 contains conserved genes belonging to the TIR-NBS-LRR class of plant resistance genes.

Relationships between proteasomes and viral gene products.

The interrelationships between proteasomes and viral gene products are very complex. 20S proteasomes associate with a number of viral mRNAs which are cleaved by proteasome's associated endonuclease activity. In addition proteasome's endopeptidase activities are involved in the presentation of viral antigens. Viral proteins of different origin associate with the 20S and 26S complexes and interfere with their enzymatic activities. A major part of this review deals with the interactions between 20S proteasomes and the gene products of the human immunodeficiency virus (HIV) which has been studied in detail by our group.

Cloning of molecular markers for disease resistance in sunflower, Helianthus annuus L.

A candidate-gene approach to analyse the resistance of plants to phytopathogenic fungi is presented. The resistance of sunflower (Helianthus annuus L.) to downy mildew (Plasmopara halstedii) shows a gene-for-gene interaction (monogenic resistance), whereas resistance to white rot (Sclerotinia sclerotiorum) is quantitative, with different levels of resistance for different plant parts. By homology cloning, probes were obtained homologous to some plant resistance genes (nucleotide binding site-like, NBS, genes and serine-threonine protein kinase-like, PK, genes). These clones were used as probes for linkage mapping of the corresponding genes. It was demonstrated that at least three NBS-like loci are located on linkage-group 1, in the region where downy mildew resistance loci have been described. Quantitative trait loci for S. sclerotiorum resistance to penetration or extension of the mycelium in different tissues were studied in three crosses. Major QTLs for resistance were found on linkage group 1, with up to 50% of the phenotypic variability explained by peaks at the map position of the PK locus, 25 cM from the downy mildew loci.

Relationships between proteasomes and RNA.

The 20S proteasome (prosome) is a highly organized multi-protein complex with approximate molecular weight of about 700 kDa. Whilst the role of the proteasome in the processing and turnover of cellular proteins is becoming clearer, its relationship with RNA remains obscure. Over the last decade the possibility of association of proteasomes with specific RNAs or mRNPs have been particularly controversial. Proteasomes were reported to inhibit translation of viral mRNAs and to be tightly associated with RNase activity. It is possible that proteasomes are also involved in cellular RNA breakdown and RNA processing like prokaryotic RNase E.

Expression of lactic dehydrogenase isoenzymes in rabbit muscle during development.

1. Rabbit cDNA probes for H and M lactic dehydrogenase subunits were used to monitor mRNA levels in different muscle types during growth. 2. At the same time, lactic dehydrogenase activity and relative quantities of H and M protein subunits were measured. 3. The main results are that mRNA abundance depends on muscle type and age, and mRNA abundance is not correlated with enzymatic activity.

A database manager of biomedical images.

In order to allow an efficient archiving and retrieval of biomedical images, PACS would include an image DBMS. As biomedical images have complex structures we developed a specific DBMS over a relational one. The medical image database manager ensures a data description that takes into account data semantics so that consistency or existential constraints may be verified. It provides a unique language to retrieve images no matter what their storage format. It encompasses the queries of the user which constitute a filter over associated data. The manager can handle changes in the environment of the image. We implemented a manager prototype to show the validity of logical access possibilities. The user need no longer know the structure of the image database to access data. The logical access allows retrieval of images, whatever the architecture of the base. An automatic query construction consists of three functional levels including the interfaces towards the external environment which ensure a logical independence from the database, a query generator which creates the correspondence between the user's query and physical access queries, a dictionary which contains the structure of the image data and consistency constraints.

Glycosylation and deglycosylation of proteasomes (prosomes) from calf-liver cells: high abundance of neuraminic acid.

Proteasomes (prosomes) of calf-liver cells were probed with three different biotinylated lectins: Limulus polyphemus agglutinin (LPA), specific for neuraminic acid; Solanum tuberosum agglutinin (STA), specific for GlcNac; and concanavalin A (Con A), specific for Man/Glc. While only one proteasomal protein reacted with STA, most of the proteasomal proteins reacted with LPA and several with Con A. Deglycosylation with N-glycosidase F showed that the detected glycan residues were asparagine-linked. Finally we demonstrate an alternative method for the isolation of proteasomes based on the affinity of certain proteasomal proteins to Con A.

Design and implementation of a biomedical image database (BDIM).

We developed a biomedical image database (BDIM) which proposes a standardized representation of value arrays such as images and curves, and of their associated parameters, independently of their acquisition mode to make their transmission and processing easier. It includes three kinds of interactions, oriented to the users. The network concept was kept as a constraint to incorporate the BDIM in a distributed structure and we maintained compatibility with the ACR/NEMA communication protocol. The management of arrays and their associated parameters includes two distinct bases of objects, linked together via a gateway. The first one manages arrays according to their storage mode: long term storage on optionally on-line mass storage devices, and, for consultations, partial copies of long term stored arrays on hard disk. The second one manages the associated parameters and the gateway by means of the relational DBMS ORACLE. Parameters are grouped into relations. Some of them are in agreement with groups defined by the ACR/NEMA. The other relations describe objects resulting from processed initial objects. These new objects are not described by the ACR/NEMA but they can be inserted as shadow groups of ACR/NEMA description. The relations describing the storage and their pathname constitute the gateway. ORACLE distributed tools and the two-level storage technique will allow the integration of the BDIM into a distributed structure, Queries and array (alone or in sequences) retrieval module has access to the relations via a level in which a dictionary managed by ORACLE is included. This dictionary translates ACR/NEMA objects into objects that can be handled by the DBMS.(ABSTRACT TRUNCATED AT 250 WORDS)

Fractures of the medial condyle of the humerus in children.

Twenty-seven cases of fractures of the medial condyle of the humerus in children were grouped into one of three types, based on displacement of the medial condyle on initial roentgenograms. Results after an average follow-up of 2.2 years showed that children less than 5 years old tended to have undisplaced fractures giving rise to good results. Older children tended to have more severely displaced fractures. Good results were obtained in patients who were seen early after injury and who had adequate reduction of their fractures. In cases seen late, proper reduction and immobilization are necessary to achieve satisfactory results.