Summary Background Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss ...of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor. Methods ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov , number NCT01891344 . Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing. Findings 256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tumours from 12 patients were established as BRCA wild-type, but could not be classified for LOH, because of insufficient neoplastic nuclei in the sample. The median duration of treatment for the 204 patients was 5·7 months (IQR 2·8–10·1). 24 patients in the BRCA mutant subgroup, 56 patients in the LOH high subgroup, and 59 patients in the LOH low subgroup had disease progression or died. Median progression-free survival after rucaparib treatment was 12·8 months (95% CI 9·0–14·7) in the BRCA mutant subgroup, 5·7 months (5·3–7·6) in the LOH high subgroup, and 5·2 months (3·6–5·5) in the LOH low subgroup. Progression-free survival was significantly longer in the BRCA mutant (hazard ratio 0·27, 95% CI 0·16–0·44, p<0·0001) and LOH high (0·62, 0·42–0·90, p=0·011) subgroups compared with the LOH low subgroup. The most common grade 3 or worse treatment-emergent adverse events were anaemia or decreased haemoglobin (45 22% patients), and elevations in alanine aminotransferase or aspartate aminotransferase (25 12%). Common serious adverse events included small intestinal obstruction (10 5% of 204 patients), malignant neoplasm progression (10 5%), and anaemia (nine 4%). Three patients died during the study (two because of disease progression and one because of sepsis and disease progression). No treatment-related deaths occurred. Interpretation In patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours. Funding Clovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer—Ovarian Cancer Research Fund Alliance—National Ovarian Cancer Coalition Dream Team Translational Research Grant, and V Foundation Translational Award.
Phenological responses to climate change (e.g., earlier leaf-out or egg hatch date) are now well documented and clearly linked to rising temperatures in recent decades. Such shifts in the phenologies ...of interacting species may lead to shifts in their synchrony, with cascading community and ecosystem consequences. To date, single-system studies have provided no clear picture, either finding synchrony shifts may be extremely prevalent Mayor SJ, et al. (2017) Sci Rep 7:1902 or relatively uncommon Iler AM, et al. (2013) Glob Chang Biol 19:2348–2359, suggesting that shifts toward asynchrony may be infrequent. A meta-analytic approach would provide insights into global trends and how they are linked to climate change. We compared phenological shifts among pairwise species interactions (e.g., predator–prey) using published long-term time-series data of phenological events from aquatic and terrestrial ecosystems across four continents since 1951 to determine whether recent climate change has led to overall shifts in synchrony. We show that the relative timing of key life cycle events of interacting species has changed significantly over the past 35 years. Further, by comparing the period before major climate change (pre-1980s) and after, we show that estimated changes in phenology and synchrony are greater in recent decades. However, there has been no consistent trend in the direction of these changes. Our findings show that there have been shifts in the timing of interacting species in recent decades; the next challenges are to improve our ability to predict the direction of change and understand the full consequences for communities and ecosystems.
Earlier spring phenology observed in many plant species in recent decades provides compelling evidence that species are already responding to the rising global temperatures associated with ...anthropogenic climate change. There is great variability among species, however, in their phenological sensitivity to temperature. Species that do not phenologically "track" climate change may be at a disadvantage if their growth becomes limited by missed interactions with mutualists, or a shorter growing season relative to earlier-active competitors. Here, we set out to test the hypothesis that phenological sensitivity could be used to predict species performance in a warming climate, by synthesizing results across terrestrial warming experiments. We assembled data for 57 species across 24 studies where flowering or vegetative phenology was matched with a measure of species performance. Performance metrics included biomass, percent cover, number of flowers, or individual growth. We found that species that advanced their phenology with warming also increased their performance, whereas those that did not advance tended to decline in performance with warming. This indicates that species that cannot phenologically "track" climate may be at increased risk with future climate change, and it suggests that phenological monitoring may provide an important tool for setting future conservation priorities.
Disruption of the plasma membrane often accompanies cellular injury, and in muscle, plasma membrane resealing is essential for efficient recovery from injury. Muscle contraction, especially of ...lengthened muscle, disrupts the sarcolemma. To define the molecular machinery that directs repair, we applied laser wounding to live mammalian myofibers and assessed translocation of fluorescently tagged proteins using high-resolution microscopy. Within seconds of membrane disruption, annexins A1, A2, A5, and A6 formed a tight repair "cap." Actin was recruited to the site of damage, and annexin A6 cap formation was both actin dependent and Ca(2+) regulated. Repair proteins, including dysferlin, EHD1, EHD2, MG53, and BIN1, localized adjacent to the repair cap in a "shoulder" region enriched with phosphatidlyserine. Dye influx into muscle fibers lacking both dysferlin and the related protein myoferlin was substantially greater than control or individual null muscle fibers, underscoring the importance of shoulder-localized proteins. These data define the cap and shoulder as subdomains within the repair complex accumulating distinct and nonoverlapping components.
Orientia tsutsugamushi is a clinically important but neglected obligate intracellular bacterial pathogen of the Rickettsiaceae family that causes the potentially life-threatening human disease scrub ...typhus. In contrast to the genome reduction seen in many obligate intracellular bacteria, early genetic studies of Orientia have revealed one of the most repetitive bacterial genomes sequenced to date. The dramatic expansion of mobile elements has hampered efforts to generate complete genome sequences using short read sequencing methodologies, and consequently there have been few studies of the comparative genomics of this neglected species.
We report new high-quality genomes of O. tsutsugamushi, generated using PacBio single molecule long read sequencing, for six strains: Karp, Kato, Gilliam, TA686, UT76 and UT176. In comparative genomics analyses of these strains together with existing reference genomes from Ikeda and Boryong strains, we identify a relatively small core genome of 657 genes, grouped into core gene islands and separated by repeat regions, and use the core genes to infer the first whole-genome phylogeny of Orientia.
Complete assemblies of multiple Orientia genomes verify initial suggestions that these are remarkable organisms. They have larger genomes compared with most other Rickettsiaceae, with widespread amplification of repeat elements and massive chromosomal rearrangements between strains. At the gene level, Orientia has a relatively small set of universally conserved genes, similar to other obligate intracellular bacteria, and the relative expansion in genome size can be accounted for by gene duplication and repeat amplification. Our study demonstrates the utility of long read sequencing to investigate complex bacterial genomes and characterise genomic variation.
NRG Oncology RTOG 0937 is a randomized phase II trial evaluating 1-year overall survival (OS) with prophylactic cranial irradiation (PCI) or PCI plus consolidative radiation therapy (PCI+cRT) to ...intrathoracic disease and extracranial metastases for extensive-disease SCLC.
Patients with one to four extracranial metastases were eligible after a complete response or partial response to chemotherapy. Randomization was to PCI or PCI+cRT to the thorax and metastases. Original stratification included partial response versus complete response after chemotherapy and one versus two to four metastases; age younger than 65 years versus 65 years or older was added after an observed imbalance. PCI consisted of 25 Gy in 10 fractions. cRT consisted of 45 Gy in 15 fractions. To detect an improvement in OS from 30% to 45% with a 34% hazard reduction (hazard ratio = 0.66) under a 0.1 type 1 error (one sided) and 80% power, 154 patients were required.
A total of 97 patients were randomized between March 2010 and February 2015. Eleven patients were ineligible (nine in the PCI group and two in the PCI+cRT group), leaving 42 randomized to receive PCI and 44 to receive PCI+cRT. At planned interim analysis, the study crossed the futility boundary for OS and was closed before meeting the accrual target. Median follow-up was 9 months. The 1-year OS was not different between the groups: 60.1% (95% confidence interval CI: 41.2–74.7) for PCI and 50.8% (95% CI: 34.0–65.3) for PCI+cRT (p = 0.21). The 3- and 12-month rates of progression were 53.3% and 79.6% for PCI and 14.5% and 75% for PCI+cRT, respectively. Time to progression favored PCI+cRT (hazard ratio = 0.53, 95% CI: 0.32–0.87, p = 0.01). One patient in each arm had grade 4 therapy-related toxicity and one had grade 5 therapy-related pneumonitis with PCI+cRT.
OS exceeded predictions for both arms. cRT delayed progression but did not improve 1-year OS.
Exposure to intense sound or noise can result in purely temporary threshold shift (TTS), or leave a residual permanent threshold shift (PTS) along with alterations in growth functions of auditory ...nerve output. Recent research has revealed a number of mechanisms that contribute to noise-induced hearing loss (NIHL). The principle cause of NIHL is damage to cochlear hair cells and associated synaptopathy. Contributions to TTS include reversible damage to hair cell (HC) stereocilia or synapses, while moderate TTS reflects protective purinergic hearing adaptation. PTS represents permanent damage to or loss of HCs and synapses. While the substrates of HC damage are complex, they include the accumulation of reactive oxygen species and the active stimulation of intracellular stress pathways, leading to programmed and/or necrotic cell death. Permanent damage to cochlear neurons can also contribute to the effects of NIHL, in addition to HC damage. These mechanisms have translational potential for pharmacological intervention and provide multiple opportunities to prevent HC damage or to rescue HCs and spiral ganglion neurons that have suffered injury. This paper reviews advances in our understanding of cellular mechanisms that contribute to NIHL and their potential for therapeutic manipulation.
•Recent research has identified many cellular mechanisms that contribute to cochlear damage and noise-induced hearing loss.•In addition, protective pathways that oppose cochlear damage mechanisms have been discovered.•Many of these mechanisms can be manipulated pharmacologically, pointing the way to potential new therapies.
BACKGROUND:Although the Affordable Care Act has been successful in expanding Medicaid to >17 million people, insurance alone may not translate into access to health care. Even among the insured, ...substantial barriers to accessing services inhibit health care utilization.
OBJECTIVES:We examined the effect of selected barriers to health care access and the magnitude of those barriers on health care utilization.
RESEARCH DESIGN:Data come from a 2008 survey of adult enrollees in Minnesota’s public health care programs. We used multivariate logistic regression to estimate the effects of perceived patient, provider, and system-level barriers on past year delayed, foregone, and lack of preventive care.
SUBJECTS:A total of 2194 adults enrolled in Minnesota Health Care Programs who were mostly female (66%), high school graduates (76%), unemployed (62%), and living in metro areas (67%) were included in the analysis.
RESULTS:Reporting problems across all barriers increased the odds of delayed care from 2 times for provider-related barriers (OR=2.0; 95% CI, 1.2–3.3) to >6 times for access barriers (OR=6.2; 95% CI, 3.8–10.2) and foregone care from 2.6 times for family/work barriers (OR=2.6; 95% CI, 1.3–5.1) to >7 times for access barriers (OR=7.1; 95% CI, 3.9–13.1). Perceived discrimination was the only barrier consistently associated with all 3 utilization outcomes.
CONCLUSIONS:Multiple types of barriers are associated with delayed and foregone care. System-level barriers and discrimination have the greatest effect on health care seeking behavior.
Phylogenetic conservatism in plant phenology Davies, T. Jonathan; Wolkovich, Elizabeth M.; Kraft, Nathan J. B. ...
The Journal of ecology,
November 2013, Letnik:
101, Številka:
6
Journal Article
Recenzirano
Odprti dostop
1. Phenological events - defined points in the life cycle of a plant or animal - have been regarded as highly plastic traits, reflecting flexible responses to various environmental cues. 2. The ...ability of a species to track, via shifts in phenological events, the abiotic environment through time might dictate its vulnerability to future climate change. Understanding the predictors and drivers of phenological change is therefore critical. 3. Here, we evaluated evidence for phylogenetic conservatism - the tendency for closely related species to share similar ecological and biological attributes - in phenological traits across flowering plants. We aggregated published and unpublished data on timing of first flower and first leaf, encompassing ~4000 species at 23 sites across the Northern Hemisphere. We reconstructed the phylogeny for the set of included species, first, using the software program Phylomatic, and second, from DNA data. We then quantified phylogenetic conservatism in plant phenology within and across sites. 4. We show that more closely related species tend to flower and leaf at similar times. By contrasting mean flowering times within and across sites, however, we illustrate that it is not the time of year that is conserved, but rather the phenological responses to a common set of abiotic cues. 5. Our findings suggest that species cannot be treated as statistically independent when modelling phenological responses. 6. Synthesis. Closely related species tend to resemble each other in the timing of their life-history events, a likely product of evolutionarily conserved responses to environmental cues. The search for the underlying drivers of phenology must therefore account for species' shared evolutionary histories.
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