Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. The WINTHER trial () navigated patients to therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The clinical management committee (investigators from five countries) recommended therapies, prioritizing genomic matches; physicians determined the therapy given. Matching scores were calculated post-hoc for each patient, according to drugs received: for DNA, the number of alterations matched divided by the total alteration number; for RNA, expression-matched drug ranks. Overall, 303 patients consented; 107 (35%; 69 in arm A and 38 in arm B) were evaluable for therapy. The median number of previous therapies was three. The most common diagnoses were colon, head and neck, and lung cancers. Among the 107 patients, the rate of stable disease ≥6 months and partial or complete response was 26.2% (arm A: 23.2%; arm B: 31.6% (P=0.37)). The patient proportion with WINTHER versus previous therapy progression-free survival ratio of >1.5 was 22.4%, which did not meet the pre-specified primary end point. Fewer previous therapies, better performance status and higher matching score correlated with longer progression-free survival (all P<0.05, multivariate). Our study shows that genomic and transcriptomic profiling are both useful for improving therapy recommendations and patient outcome, and expands personalized cancer treatment.

SummaryAlternative splicing (AS) combines different transcript splice junctions that result in transcripts with shuffled exons, alternative 5¢ or 3¢ splicing sites, retained introns and different transcript termini. In this way, multiple mRNA species and proteins can be created from a single gene expanding the potential informational content of eukaryotic genomes. Search algorithms of AS forms in a variety of Arabidopsis databases showed they contained an unusually high fraction of retained introns (above 30%), compared with 10% that was reported for humans. The preponderance of retained introns (65%) were either part of open reading frames, present in the UTR region or present as the last intron in the transcript, indicating that their occurrence would not participate in non-sense-mediated decay. Interestingly, the functional distribution of the transcripts with retained introns is skewed towards stress and external/internal stimuli-related functions. A sampling of the alternative transcripts with retained introns were confirmed by RT-PCR and were shown to co-purify with polyribosomes, indicating their nuclear export. Thus, retained introns are a prominent feature of AS in Arabidopsis and as such may play a regulatory function.

OBJECTIVELong-term dietary intervention frequently induces a rapid weight decline followed by weight stabilization/regain. Here, we sought to identify adipokine biomarkers that may reflect continued beneficial effects of dieting despite partial weight regain.RESEARCH DESIGN AND METHODSWe analyzed the dynamics of fasting serum levels of 12 traditional metabolic biomarkers and novel adipokines among 322 participants in the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT) of low-fat, Mediterranean, or low-carbohydrate diets for weight loss.RESULTSWe identified two distinct patterns: Pattern A includes biomarkers (insulin, triglycerides, leptin, chemerin, monocyte chemoattractant protein 1, and retinol-binding protein 4) whose dynamics tightly correspond to changes in body weight, with the trend during the weight loss phase (months 0–6) going in the opposite direction to that in the weight maintenance/regain phase (months 7–24) (P < 0.05 between phases, all biomarkers). Pattern B includes biomarkers (high molecular weight adiponectin, HDL cholesterol [HDL-C], high-sensitivity C-reactive protein [hsCRP], fetuin-A, progranulin, and vaspin) that displayed a continued, cumulative improvement (P < 0.05 compared with baseline, all biomarkers) throughout the intervention. These patterns were consistent across sex, diabetic groups, and diet groups, although the magnitude of change varied. Hierarchical analysis suggested similar clusters, revealing that the dynamic of leptin (pattern A) was most closely linked to weight change and that the dynamic of hsCRP best typified pattern B.CONCLUSIONShsCRP, HDL-C, adiponectin, fetuin-A, progranulin, and vaspin levels display a continued long-term improvement despite partial weight regain. This may likely reflect either a delayed effect of the initial weight loss or a continuous beneficial response to switching to healthier dietary patterns.

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The mechanism by which the maize autonomous Ac transposable element gives rise to nonautonomous Ds elements is largely unknown. Sequence analysis of native maize Ds elements indicates a complex chimeric structure formed through deletions of Ac sequences with or without insertions of Ac-unrelated sequence blocks. These blocks are often flanked by short stretches of reshuffled and duplicated Ac sequences. To better understand the mechanism leading to Ds formation, we designed an assay for detecting alterations in Ac using transgenic tobacco plants carrying a single copy of Ac. We found frequent de novo alterations in Ac which were excision rather than sequence dependent, occurring within Ac but not within an almost identical Ds element and not within a stable transposase-producing gene. The de novo DNA rearrangements consisted of internal deletions with breakpoints usually occurring at short repeats and, in some cases, of duplication of Ac sequences or insertion of Ac-unrelated fragments. The ancient maize Ds elements and the young Ds elements in transgenic tobacco showed similar rearrangements, suggesting that Ac-Ds elements evolve rapidly, more so than stable genes, through deletions, duplications, and reshuffling of their own sequences and through capturing of unrelated sequences. The data presented here suggest that abortive Ac-induced gap repair, through the synthesis-dependent strand-annealing pathway, is the underlying mechanism for Ds element formation.Dissociation, or Ds, is the first discovered transposable element (TE). It was identified as a maize locus on chromosome 9, where breaks occur in the presence of Activator (Ac), a second gene found at a separate locus (33,34). Subsequent studies showed that Ac can transpose autonomously whereas Ds moves only in the presence of Ac (35,36). In addition, Ac activity can turn into a Ds type of instability, while no occurrences were found of Ds turning into Ac (37, 38). On the basis of these observations, McClintock proposed that Ds nonautonomous elements are derived from Ac through mutations (39). The proposal that Ac and Ds are phylogenetically related has been supported by molecular analysis, as described below, but the mechanism responsible for the conversion of Ac into Ds is still unknown.Ac is a 4.6-kb-long element flanked by 11-bp terminal inverted repeats (TIRs) (12). It encodes an 807-amino-acid protein, the transposase, necessary for both Ac and Ds transposition (28). Ds elements, on the other hand, do not encode a functional transposase but retain regions which are essential for their transposition (6). There are six fully sequenced Ds elements, all of which share with Ac nearly identical TIRs and fall into the following four categories: (i) those with nearly no similarity to Ac, like Ds1 (57); (ii) elements with highly similar subterminal regions but with internal deletions, like Ds9 (46); (iii) double Ds elements where one internally deleted Ds is inserted into another identical Ds in an inverted orientation (9); and (iv) Ds elements that contain bot...