Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge. PATIENTS AND METHODS: This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint. RESULTS: Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge. CONCLUSIONS: In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.

Multistage coupling of independent laser-plasma accelerators.

Laser-plasma accelerators (LPAs) are capable of accelerating charged particles to very high energies in very compact structures. In theory, therefore, they offer advantages over conventional, large-scale particle accelerators. However, the energy gain in a single-stage LPA can be limited by laser diffraction, dephasing, electron-beam loading and laser-energy depletion. The problem of laser diffraction can be addressed by using laser-pulse guiding and preformed plasma waveguides to maintain the required laser intensity over distances of many Rayleigh lengths; dephasing can be mitigated by longitudinal tailoring of the plasma density; and beam loading can be controlled by proper shaping of the electron beam. To increase the beam energy further, it is necessary to tackle the problem of the depletion of laser energy, by sequencing the accelerator into stages, each powered by a separate laser pulse. Here, we present results from an experiment that demonstrates such staging. Two LPA stages were coupled over a short distance (as is needed to preserve the average acceleration gradient) by a plasma mirror. Stable electron beams from a first LPA were focused to a twenty-micrometre radius--by a discharge capillary-based active plasma lens--into a second LPA, such that the beams interacted with the wakefield excited by a separate laser. Staged acceleration by the wakefield of the second stage is detected via an energy gain of 100 megaelectronvolts for a subset of the electron beam. Changing the arrival time of the electron beam with respect to the second-stage laser pulse allowed us to reconstruct the temporal wakefield structure and to determine the plasma density. Our results indicate that the fundamental limitation to energy gain presented by laser depletion can be overcome by using staged acceleration, suggesting a way of reaching the electron energies required for collider applications.

The face of postural tachycardia syndrome - insights from a large cross-sectional online community-based survey.

BACKGROUND: Patients with postural tachycardia syndrome (POTS) experience chronic symptoms of orthostatic intolerance. There are minimal data detailing the demographics, clinical features and clinical course of this condition. This online, community-based survey highlights patients' experience with POTS. It consists of the largest sample of POTS patients reported to date. OBJECTIVES: To describe the demographics, past medical history, medications, treatments and diagnostic journey for patients living with POTS. METHODS: Postural tachycardia syndrome patients completed an online, community-based, cross-sectional survey. Participants were excluded if they had not received a diagnosis of POTS from a physician. The questions focused on the patient experience and journey, rather than physiological responses. RESULTS: The final analysis included 4835 participants. POTS predominantly affects white (93%) females (94%) of childbearing age, with approximately half developing symptoms in adolescence (mode 14 years). POTS is a chronic multisystem disorder involving a broad array of symptoms, with many patients diagnosed with comorbidities in addition to POTS. POTS patients often experience lengthy delays [median (interquartile range) 24 (6-72) months] and misdiagnosis, but the diagnostic delay is improving. POTS patients can present with a myriad of symptoms most commonly including lightheadedness (99%), tachycardia (97%), presyncope (94%), headache (94%) and difficulty concentrating (94%). CONCLUSIONS: These data provide important insights into the background, clinical features and diagnostic journey of patients suffering from POTS. These data should serve as an essential step for moving forward with future studies aimed at early and accurate diagnoses of these patients leading to appropriate treatments for their symptoms.

Clathrin localization and dynamics in Aspergillus nidulans.

Cell growth necessitates extensive membrane remodeling events including vesicle fusion or fission, processes that are regulated by coat proteins. The hyphal cells of filamentous fungi concentrate both exocytosis and endocytosis at the apex. This investigation focuses on clathrin in Aspergillus nidulans, with the aim of understanding its role in membrane remodeling in growing hyphae. We examined clathrin heavy chain (ClaH-GFP) which localized to three distinct subcellular structures: late Golgi (trans-Golgi equivalents of filamentous fungi), which are concentrated just behind the hyphal tip but are intermittently present throughout all hyphal cells; the region of concentrated endocytosis just behind the hyphal apex (the "endocytic collar"); and small, rapidly moving puncta that were seen trafficking long distances in nearly all hyphal compartments. ClaH localized to distinct domains on late Golgi, and these clathrin "hubs" dispersed in synchrony after the late Golgi marker PHOSBP . Although clathrin was essential for growth, ClaH did not colocalize well with the endocytic patch marker fimbrin. Tests of FM4-64 internalization and repression of ClaH corroborated the observation that clathrin does not play an important role in endocytosis in A. nidulans. A minor portion of ClaH puncta exhibited bidirectional movement, likely along microtubules, but were generally distinct from early endosomes.

Effect of ageing on the calibration of ballistic gelatin.

PURPOSE: Ballistic gelatin is commonly used as a validated surrogate for soft tissue during terminal ballistic testing. However, the effect of a delay between production and testing of a gelatin mould remains unknown. The aim of this study was to determine any potential effects of ageing on ballistic gelatin. METHODS: Depth of penetration (DoP) of 4.5 mm spherical fragment simulating projectiles was ascertained using mixtures of 10%, 11.25% and 20% Type A 250 Bloom ballistic gelatin. Testing was performed daily for 5 days using velocities between 75 and 210 m/s. DoP at day 5 was statistically compared with day 1, and net mass change was recorded daily. RESULTS: No significant difference was found for DoP observed with time in any of the samples (P>0.05). Spearman correlation was excellent in all moulds. The moulds with known standard calibrations remained in calibration throughout the study period. Mass loss of less than 1% was noted in all samples. CONCLUSION: Mass loss was the only quantifiable measure of changes in the blocks with time, but did not correlate with any changes in DoP. This may provide reassurance when undertaking such testing that an inadvertent delay will not significantly alter the penetration properties of the mould. Future research is recommended to determine any potential effect on the mechanical properties of gelatin at higher velocity impacts and whether the calibration corresponds to an adequate simulation under such conditions.

Influence of rib impact on thoracic gunshot trauma.

INTRODUCTION: The influence of rib impact on thoracic gunshot trauma remains unclear, despite its high occurrence. This study therefore investigates the effect of rib impact on a bullet's terminal properties and injury severity. METHODS: Two bullets were used: 5.56×45 mm (full charge and reduced charge) and 7.62×51 mm (full charge). For each bullet, three impact groups were tested: (1) plain 10% ballistic gelatin (control) conditioned at 4°C, (2) intercostal impact, and (3) rib impact, the latter two tested with samples of porcine thoracic walls embedded in gelatin. Analysis included penetration depth, trajectory change, yaw, fragmentation, velocity reduction, energy deposition and temporary and permanent cavity characteristics. RESULTS: No significant differences were observed for most variables. Differences were found between rib (and intercostal) impact and the control groups, suggesting that the inclusion of thoracic walls produces an effect more significant than the anatomical impact site. Effects were ammunition specific. For the 7.62×51 mm round, rib impact caused an earlier onset of yaw and more superficial permanent gelatin damage compared with plain gelatin. This round also formed a larger temporary cavity on rib impact than intercostal impact. Rib (and intercostal impact) created a smaller temporary cavity than the control for the 5.56×45 mm round. For the reduced-charge 5.56×45 mm round, rib and intercostal impact produced greater velocity reduction compared with plain gelatin. CONCLUSIONS: This study provides new insights into the role of rib impact in thoracic gunshot injuries, and indicates that the effects are ammunition dependent. Unlike the 5.56×45 mm rounds, rib impact with the 7.62×51 mm rounds increases the risk of severe wounding.

Meeting American Diabetes Association diabetes management targets: trends in Mauritius.

AIMS: To examine the proportion of people with diabetes in the multi-ethnic country of Mauritius meeting American Diabetes Association targets in 2009 and 2015. METHODS: Data from independent population-based samples of 858 and 656 adults with diagnosed diabetes in 2009 and 2015, respectively, were analysed with regard to recommended American Diabetes Association targets for HbA1c , blood pressure and LDL cholesterol. RESULTS: In 2015 compared with 2009, the proportion of people achieving American Diabetes Association targets for glycaemic control in Mauritius was higher in women (P≤0.01) and in those with only a primary education level (P=0.07), but not in men or people with a higher level of education. Achievement of blood pressure <140/90 mmHg was higher in 2015 compared with 2009 (60% vs 42%) in people of South Asian ethnicity (P<0.001), but not in those of African ethnicity (P=0.16). The percentages of people with LDL cholesterol <2.59 mmol/l were 42.1% and 50.4%, in 2009 and 2015, respectively (P=0.27). Better control of HbA1c and blood pressure was observed in groups in which that control was poorest in 2009. The use of glucose-, blood pressure- and LDL cholesterol-lowering medication was higher in 2015 than in 2009. CONCLUSIONS: In certain subgroups, namely women, those with poorer education and those of South Asian ethnicity, whose target achievement was the poorest in 2009, control of glycaemia and blood pressure was better in 2015 as compared with 2009. While these findings are encouraging, further work is required to improve outcomes.

Diffusion Barriers Block Defect Occupation on Reduced CeO_{2}(111).

Surface defects are believed to govern the adsorption behavior of reducible oxides. We challenge this perception on the basis of a combined scanning-tunneling-microscopy and density-functional-theory study, addressing the Au adsorption on reduced CeO_{2-x}(111). Despite a clear thermodynamic preference for oxygen vacancies, individual Au atoms were found to bind mostly to regular surface sites. Even at an elevated temperature, aggregation at step edges and not decoration of defects turned out to be the main consequence of adatom diffusion. Our findings are explained with the polaronic nature of the Au-ceria system, which imprints a strong diabatic character onto the diffusive motion of adatoms. Diabatic barriers are generally higher than those in the adiabatic regime, especially if the hopping step couples to an electron transfer into the ad-gold. As the population of O vacancies always requires a charge exchange, defect decoration by Au atoms becomes kinetically hindered. Our study demonstrates that polaronic effects determine not only electron transport in reducible oxides but also the adsorption characteristics and therewith the surface chemistry.

Computational prediction and experimental validation of a novel miRNA in Suaeda maritima, a halophyte.

The lack of available transcriptome data for plants of no economic or agronomic importance limits the identification of miRNAs in many species. Considering the possible similarity of the transcriptome between related species, the present study used expressed sequence tags (ESTs) of Suaeda salsa and Suaeda glauca to identify conserved miRNAs, which were validated in a halophyte, Suaeda maritima, with the aim of identifying salt-responsive miRNAs from naturally salt-tolerant plants, information on which is limited. In this study, computational analysis predicted three miRNA sequences by mapping non-redundant miRNA sequences from miRBase 16.0 on 1534 ESTs of S. salsa and S. glauca. The expression of one could be validated in S. maritima, and was named sma-miR1867. This miRNA was downregulated in response to NaCl treatment. It was predicted to target ferredoxin-thioredoxin reductase (FTR), cell division control protein 6 (CDC6), and ubiquitin-protein ligase (UPL) in S. salsa and/or S. glauca. However, only UPL could be amplified in S. maritima, and RT-qPCR showed that it was upregulated in response to NaCl treatment. These results indicate that, in halophytes, FTR and CDC6 may promote carbon metabolism and cell division, respectively, in the presence of salt, while UPL may regulate the abundance of proteins that are important for salt tolerance in halophytes. Thus, sma-miR1867 could be an essential component of salt resistance in halophytes.

Novel alleles of the transforming growth factor ß-1 regulatory region and exon 1.

Transforming growth factor ß-1, encoded by the TGFB1 gene, is a cytokine that plays a central role in many physiologic and pathogenic processes with pleiotropic effects. Regulatory activity for this gene has been shown for 3.0 kb between positions -2665 and +423 from its translational start site. At least 17 TGFB1 regulatory region and exon 1 alleles have been defined on the basis of 18 polymorphic sites. Polymorphisms in TGFB1's regulatory region have been associated with differential levels of expression of this cytokine and to genetic risk in cancer and transplantation. In this report, we present 19 novel TGFB1 regulatory region and exon 1 alleles: p018-p036. Amplification of TGFB1's regulatory region was performed with an in-house protocol, and novel alleles were defined by either allele-specific amplification and/or molecular cloning of the amplicons, followed by sequencing in isolation. Three of these novel alleles (p018, p019, and p020) are shown to be formed by novel combinations of the aforementioned known polymorphic positions. Another 16 novel alleles are shown to carry additional known and unknown single-nucleotide polymorphisms. Polymorphism in TGFB1's regulatory region could have an impact on important processes, including embryogenesis, hematopoiesis, carcinogenesis, angiogenesis, fibrosis, immune responses, and transplantation, making its characterization necessary.

Active Plasma Lensing for Relativistic Laser-Plasma-Accelerated Electron Beams.

Compact, tunable, radially symmetric focusing of electrons is critical to laser-plasma accelerator (LPA) applications. Experiments are presented demonstrating the use of a discharge-capillary active plasma lens to focus 100-MeV-level LPA beams. The lens can provide tunable field gradients in excess of 3000 T/m, enabling cm-scale focal lengths for GeV-level beam energies and allowing LPA-based electron beams and light sources to maintain their compact footprint. For a range of lens strengths, excellent agreement with simulation was obtained.

Real time PCR expression analysis of gene encoding p5cs enzyme and proline metabolism under NaCI salinity in rice.

Regulation of proline accumulation in seedlings of rice (Oryza sativa L. cv. Lunishree) was investigated. The increasing concentration of NaCl from 85 mM to 425 mM NaCl progressively increased proline content in rice. The maximum increase in proline content was recorded at 425 mM NaCl concentration as compared to control and other concentrations of NaCl. The highest significant activity of proline synthesizing enzymes, delta1-Pyrrolline-5-carboxylate synthetase, delta1-Pyrrolline-5-carboxylate reductase and Ornithine-δ- aminotransferase with lowest activity of proline hydrolysis enzymes;Proline dehydrogenase was also recorded at 425 mM NaCl salinity over control and other concentrations of NaCI with insignificant increase in the activity of delta1-Pyrrolline-5-carboxylate synthetase and Ornithine-δ-aminotransferase at 85 mM NaCI over control. It was found that the transcript of gene encoded with p5cs is up regulated about 1.35 folds under salinity stress. This gene synthesis an osmo protectant to help the plant resist the change in osmotic imbalances. Externally addition of MnCl2 at 300 mg/220 ml 1/2 strength Hoagland solution, having 1% NaCI, was also seen to increase 893.9% proline content of this variety as compared to control.

A novel HLA-A allele, A*74:23, identified in an individual from Costa Rica.

The new HLA-A*74:23 allele differs from the closest allele A*74:01 by a nucleotide change in exon 3 at codon 97.

Spectral characterization of laser-driven solid-based high harmonics in the coherent wake emission regime.

Laser-produced surface high-harmonic generation is an attractive source of extreme ultraviolet radiation due to its coherent properties and high peak power. By operating at subrelativistic laser intensities in the coherent wake emission regime, the harmonic spectrum was experimentally studied versus laser properties. At higher laser intensities (>10(17) W/cm(2)) a higher spectral cutoff was observed, with accompanying blueshifting and spectral broadening of the individual orders. A model based on an expanding critical surface provides qualitative agreement with the observations.

Efficient inscription of Bragg gratings in As2S3 fibers using near bandgap light.

Efficient inscription of Fiber Bragg gratings (FBGs) in single-mode, thin cladding As(2)S(3) fibers is demonstrated by using near bandgap light at 532 nm. The FBGs with the reflectivity of over 80% can be induced in only 80-90 s, substantially faster than in previous reports. The dynamics of the grating growth are investigated in the photosensitivity process, showing a fast blue shift of the Bragg wavelength and then a somewhat slower red shift. The aging of the grating after fabrication is also reported, indicating a 37% decay of the grating strength.

Inbreeding depression in self-incompatible North-American Arabidopsis lyrata: disentangling genomic and S-locus-specific genetic load.

Newly formed selfing lineages may express recessive genetic load and suffer inbreeding depression. This can have a genome-wide genetic basis, or be due to loci linked to genes under balancing selection. Understanding the genetic architecture of inbreeding depression is important in the context of the maintenance of self-incompatibility and understanding the evolutionary dynamics of S-alleles. We addressed this using North-American subspecies of Arabidopsis lyrata. This species is normally self-incompatible and outcrossing, but some populations have undergone a transition to selfing. The goals of this study were to: (1) quantify the strength of inbreeding depression in North-American populations of A. lyrata; and (2) disentangle the relative contribution of S-linked genetic load compared with overall inbreeding depression. We enforced selfing in self-incompatible plants with known S-locus genotype by treatment with CO(2), and compared the performance of selfed vs outcrossed progeny. We found significant inbreeding depression for germination rate (δ=0.33), survival rate to 4 weeks (δ=0.45) and early growth (δ=0.07), but not for flowering rate. For two out of four S-alleles in our design, we detected significant S-linked load reflected by an under-representation of S-locus homozygotes in selfed progeny. The presence or absence of S-linked load could not be explained by the dominance level of S-alleles. Instead, the random nature of the mutation process may explain differences in the recessive deleterious load among lineages.

16th IHIW: international histocompatibility working group in hematopoietic cell transplantation.

The International Histocompatibility Working Group is a collaborative international effort to understand the HLA and non-HLA genetics of the transplantation barrier. The Working Group is comprised of experts in the fields of histocompatibility and immunogenetics, hematopoietic cell transplantation and outcomes research. Data for 25 855 unrelated donor transplants were submitted in support of research studies for the 16th International Histocompatibility Workshop. Active investigation is in progress in seven key areas: the impact of HLA matching, role of race and ethnicity, identification of permissible HLA mismatches, haplotype-associated determinants, minor histocompatibility antigens, immune response genes and KIR genetics. New hypotheses for the 16th workshop were developed for immunogenetic studies in cord blood and haploidentical-related donor transplantation.

Effects of a mat Pilates programme on body composition in elderly women.

BACKGROUND: With ageing, the ability to mobilize fat is reduced and this, coupled with gradual decrease in lean body mass (LBM) from lessened exercise, allows for an increased body fat percentage (%BF). Exercising is considered a key to maintaining an appropriate body mass (BM), as it improves fat oxidation, while maintaining LBM. Although the effects of endurance and/or resistance training on fat mass (FM) and LBM in the elderly have well been established, limited data are forthcoming regarding the effects of Pilates as a training modality on these variables in the elderly. OBJECTIVE: The present study was therefore conducted to determine the effects of a mat Pilates programme on body fat in elderly women. METHODS: Fifty sedentary, apparently healthy females aged 60 years and older were randomly assigned a control (CG, n = 25) or an intervention (IG, n = 25) group. The IG took part in an eight-week progressive mat Pilates exercise programme, three times weekly while the CG were instructed to maintain their normal daily activities throughout the eight-week experimental period. All subjects underwent pre- and post-test in which FM and LBM were assessed. RESULTS: Eight weeks of mat Pilates demonstrated a significant (p ≤ 0.05) decrease in % BF (p = 0.016) and FM (p = 0.038), with a significant increase in LBM (p = 0.006), while not showing any significant changes (p ≥ 0.05) in BM (p = 0.979) and BMI (p = 0.992). The CG, however, did not produce any significant (p ≥ 0.05) changes in any of the tested anthropometric variables (BM: p = 0.266; BMI: p = 0.123; % BF: p = 0.516; FM: p = 0.937 and LBM: p = 0.522) after completion of the eight-week Pilates programme. CONCLUSION: An eight-week mat Pilates exercise programme may contradict or even reverse some of the most serious consequences of ageing associated with an increased fat mass and reduced lean body mass in elderly females.

A prediction equation for the estimation of cardiorespiratory fitness using an elliptical motion trainer.

OBJECTIVE: In the United States of America, 6.2 million individuals are using elliptical motion trainers in fitness centres. However, graded exercise test protocols to estimate peak oxygen consumption (VO(2peak)) using elliptical motion trainers have not been developed for the general population. METHODS: Fifty-nine subjects (mean age: 23.5 +/- 4.1 years) were randomly divided into a validation (VAL: n = 39) or cross-validation (XVAL: n = 20) group. Peak oxygen consumption (ml x kg(-1) x min(-1)) was measured via indirect calorimetry on an elliptical motion trainer for both groups. Subjects exercised at 150 strides x min(-1) against a resistance of four and a crossramp of 8%. The resistance was increased every two minutes by two units until exhaustion. For the VAL group, a stepwise regression analysis was used to predict VO(2peak) from resistance, maximal heart rate (HR(max)), body mass index (BMI), height and gender (female = 0, male = 1). RESULTS: The prediction equation derived from this study was VO(2peak) (ml x kg(-1) x min(-1)) = 187.39403 + 12.97271 (gender) - 1.45311 (height) - 1.21604 (BMI) - 0.19613 (HR(max)) + 1.57093 (resistance) (R2 = 0.76, SEE = 4.47, p < 0.05). Using this equation, the predicted VO(2peak) of the XVAL group was 45.18 +/- 6.42 ml x kg(-1) x min(-1), while the measured VO(2peak) was 43.55 +/- 6.23 ml x kg(-1) x min(-1) CONCLUSION: No significant difference was found between the measured and predicted VO(2peak) in the XVAL group. Therefore, it appears this protocol and equation will allow individuals to accurately estimate their VO(2peak) without using direct calorimetry. However future studies should investigate the validity of this protocol with diverse populations.