X-ray free-electron lasers enable the investigation of the structure and dynamics of diverse systems, including atoms, molecules, nanocrystals and single bioparticles, under extreme conditions. Many ...imaging applications that target biological systems and complex materials use hard X-ray pulses with extremely high peak intensities (exceeding 10
watts per square centimetre). However, fundamental investigations have focused mainly on the individual response of atoms and small molecules using soft X-rays with much lower intensities. Studies with intense X-ray pulses have shown that irradiated atoms reach a very high degree of ionization, owing to multiphoton absorption, which in a heteronuclear molecular system occurs predominantly locally on a heavy atom (provided that the absorption cross-section of the heavy atom is considerably larger than those of its neighbours) and is followed by efficient redistribution of the induced charge. In serial femtosecond crystallography of biological objects-an application of X-ray free-electron lasers that greatly enhances our ability to determine protein structure-the ionization of heavy atoms increases the local radiation damage that is seen in the diffraction patterns of these objects and has been suggested as a way of phasing the diffraction data. On the basis of experiments using either soft or less-intense hard X-rays, it is thought that the induced charge and associated radiation damage of atoms in polyatomic molecules can be inferred from the charge that is induced in an isolated atom under otherwise comparable irradiation conditions. Here we show that the femtosecond response of small polyatomic molecules that contain one heavy atom to ultra-intense (with intensities approaching 10
watts per square centimetre), hard (with photon energies of 8.3 kiloelectronvolts) X-ray pulses is qualitatively different: our experimental and modelling results establish that, under these conditions, the ionization of a molecule is considerably enhanced compared to that of an individual heavy atom with the same absorption cross-section. This enhancement is driven by ultrafast charge transfer within the molecule, which refills the core holes that are created in the heavy atom, providing further targets for inner-shell ionization and resulting in the emission of more than 50 electrons during the X-ray pulse. Our results demonstrate that efficient modelling of X-ray-driven processes in complex systems at ultrahigh intensities is feasible.
Purpose
In LOTUS (NCT02162719), adding the oral AKT inhibitor ipatasertib to first-line paclitaxel for locally advanced/metastatic triple-negative breast cancer (aTNBC) improved progression-free ...survival (PFS; primary endpoint), with an enhanced effect in patients with
PIK3CA/AKT1/PTEN
-altered tumors (FoundationOne next-generation sequencing NGS assay). We report final overall survival (OS) results.
Methods
Eligible patients had measurable previously untreated aTNBC. Patients were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status, and were randomized 1:1 to paclitaxel 80 mg/m
2
(days 1, 8, 15) plus ipatasertib 400 mg or placebo (days 1–21) every 28 days until disease progression or unacceptable toxicity. OS (intent-to-treat ITT, immunohistochemistry PTEN-low, and PI3K/AKT pathway-activated NGS
PIK3CA/AKT1/PTEN
-altered populations) was a secondary endpoint.
Results
Median follow-up was 19.0 versus 16.0 months in the ipatasertib–paclitaxel versus placebo–paclitaxel arms, respectively. In the ITT population (
n
= 124), median OS was numerically longer with ipatasertib–paclitaxel than placebo–paclitaxel (hazard ratio 0.80, 95% CI 0.50–1.28; median 25.8 vs 16.9 months, respectively; 1-year OS 83% vs 68%). Likewise, median OS favored ipatasertib–paclitaxel in the PTEN-low (
n
= 48; 23.1 vs 15.8 months; hazard ratio 0.83) and
PIK3CA/AKT1/PTEN
-altered (
n
= 42; 25.8 vs 22.1 months; hazard ratio 1.13) subgroups. The ipatasertib–paclitaxel safety profile was unchanged.
Conclusions
Final OS results show a numerical trend favoring ipatasertib–paclitaxel and median OS exceeding 2 years with ipatasertib–paclitaxel. Overall, results are consistent with the reported PFS benefit; interpretation within biomarker-defined subgroups is complicated by small sample sizes and TNBC heterogeneity.
We present the results of an optical spectroscopic monitoring program targeting NGC 5548 as part of a larger multiwavelength reverberation mapping campaign. The campaign spanned 6 months and achieved ...an almost daily cadence with observations from five ground-based telescopes. The Hβ and He ii λ4686 broad emission-line light curves lag that of the 5100 optical continuum by and , respectively. The Hβ lag relative to the 1158 ultraviolet continuum light curve measured by the Hubble Space Telescope is ∼50% longer than that measured against the optical continuum, and the lag difference is consistent with the observed lag between the optical and ultraviolet continua. This suggests that the characteristic radius of the broad-line region is ∼50% larger than the value inferred from optical data alone. We also measured velocity-resolved emission-line lags for Hβ and found a complex velocity-lag structure with shorter lags in the line wings, indicative of a broad-line region dominated by Keplerian motion. The responses of both the Hβ and He ii emission lines to the driving continuum changed significantly halfway through the campaign, a phenomenon also observed for C iv, Ly , He ii(+O iii), and Si iv(+O iv) during the same monitoring period. Finally, given the optical luminosity of NGC 5548 during our campaign, the measured Hβ lag is a factor of five shorter than the expected value implied by the RBLR-LAGN relation based on the past behavior of NGC 5548.
Aims/hypothesis
Obesity and insulin resistance are associated with low-grade chronic inflammation. Glucagon-like peptide-1 (GLP-1) is known to reduce insulin resistance. We investigated whether GLP-1 ...has anti-inflammatory effects on adipose tissue, including adipocytes and adipose tissue macrophages (ATM).
Methods
We administered a recombinant adenovirus (rAd) producing GLP-1 (rAd-GLP-1) to an
ob/ob
mouse model of diabetes. We examined insulin sensitivity, body fat mass, the infiltration of ATM and metabolic profiles. We analysed the mRNA expression of inflammatory cytokines, lipogenic genes, and M1 and M2 macrophage-specific genes in adipose tissue by real-time quantitative PCR. We also examined the activation of nuclear factor κB (NF-κB), extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase (JNK) in vivo and in vitro.
Results
Fat mass, adipocyte size and mRNA expression of lipogenic genes were significantly reduced in adipose tissue of rAd-GLP-1-treated
ob/ob
mice. Macrophage populations (F4/80
+
and F4/80
+
CD11b
+
CD11c
+
cells), as well as the expression and production of IL-6, TNF-α and monocyte chemoattractant protein-1, were significantly reduced in adipose tissue of rAd-GLP-1-treated
ob/ob
mice. Expression of M1-specific mRNAs was significantly reduced, but that of M2-specific mRNAs was unchanged in rAd-GLP-1-treated
ob/ob
mice. NF-κB and JNK activation was significantly reduced in adipose tissue of rAd-GLP-1-treated
ob/ob
mice. Lipopolysaccharide-induced inflammation was reduced by the GLP-1 receptor agonist, exendin-4, in 3T3-L1 adipocytes and ATM.
Conclusions/interpretation
We suggest that GLP-1 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and ATM, possibly contributing to the improvement of insulin sensitivity.
Abstract Current studies have shown that living-donor liver transplantation (LDLT) for hepatocelluar carcinoma (HCC) satisfying the Milan criteria does not compromise patient survival or increase HCC ...recurrence compared with deceased-donor liver transplantation (DDLT). For patients with HCC beyond the Milan criteria, however, worse outcomes are expected after LDLT than after DDLT, despite insufficient data to reach a conclusion. Regarding operative technique, LDLT might be a less optimal cancer operation for HCC located at the hepatic vein confluence and/or paracaval portion. The closeness to the wall of the retrohepatic inferior vena cava (IVC) is greater than in conventional DDLT, rendering it difficult to perform a no-touch en bloc total hepatectomy. An LDLT, which must preserve the native IVC for the piggyback technique during engraftment, may lead to tumor remnants. To reduce recurrences after LDLT, we successfully performed a no-touch en bloc total hepatectomy including the retrohepatic IVC and all 3 hepatic veins. IVC replacement with an artificial vascular graft together with a modified right-lobe LDLT was performed for a patient having advanced HCC close to the hepatic vein confluence and paracaval portion. There was no artificial vascular graft-related complication, such as thrombosis or infection. Despite the limitations of LDLT, requiring the piggyback technique for graft implantation, IVC replacement using an artificial graft led us to perform a no-touch en bloc total hepatectomy as with a conventional DDLT.
Background: This study was to devise a prognostic model for metastatic gastric cancer patients undergoing first-line chemotherapy. Patients and methods: A retrospective analysis was carried out on ...1455 gastric cancer patients, who received first-line chemotherapy from September 1994 to February 2005. Results: At multivariate level, poor prognostic factors were no previous gastrectomy P = 0.003; relative risk (RR), 1.191; 95% confidence interval (CI) 1.061–1.338, albumin <3.6 g/dl (P = <0.001; RR, 1.245; 95% CI 1.106–1.402), alkaline phosphatase >85 U/l (P = <0.001; RR, 1.224; 95% CI 1.092–1.371), Eastern Cooperative Oncology Group performance status of two or more (P = <0.001; RR, 1.690; 95% CI 1.458–1.959), the presence of bone metastases (P = 0.001; RR, 1.460; 95% CI 1.616–1.836), and the presence of ascites (P = <0.001; RR, 1.452; 95% CI 1.295–1.628). Of 1434 patients, 489 patients (34.1%) were categorized as low-risk group (zero to one factors), 889 patients (62.0%) as intermediate-risk group (two to four factors), and 56 patients (3.9%) as high-risk group (five to six factors). Median survival durations for low, intermediate, and high-risk groups were 12.5 months, 7.0 months, and 2.7 months, respectively. Conclusions: This model should facilitate the individual patient risk stratification and thus, more appropriate therapies for each metastatic gastric cancer patient.
Abstract Finite element (FE) model studies have made important contributions to our understanding of functional biomechanics of the lumbar spine. However, if a model is used to answer clinical and ...biomechanical questions over a certain population, their inherently large inter-subject variability has to be considered. Current FE model studies, however, generally account only for a single distinct spinal geometry with one set of material properties. This raises questions concerning their predictive power, their range of results and on their agreement with in vitro and in vivo values. Eight well-established FE models of the lumbar spine (L1-5) of different research centers around the globe were subjected to pure and combined loading modes and compared to in vitro and in vivo measurements for intervertebral rotations, disc pressures and facet joint forces. Under pure moment loading, the predicted L1-5 rotations of almost all models fell within the reported in vitro ranges, and their median values differed on average by only 2° for flexion-extension, 1° for lateral bending and 5° for axial rotation. Predicted median facet joint forces and disc pressures were also in good agreement with published median in vitro values. However, the ranges of predictions were larger and exceeded those reported in vitro , especially for the facet joint forces. For all combined loading modes, except for flexion, predicted median segmental intervertebral rotations and disc pressures were in good agreement with measured in vivo values. In light of high inter-subject variability, the generalization of results of a single model to a population remains a concern. This study demonstrated that the pooled median of individual model results, similar to a probabilistic approach, can be used as an improved predictive tool in order to estimate the response of the lumbar spine.
During the Space Telescope and Optical Reverberation Mapping Project observations of NGC 5548, the continuum and emission-line variability became decorrelated during the second half of the ...six-month-long observing campaign. Here we present Swift and Chandra X-ray spectra of NGC 5548 obtained as part of the campaign. The Swift spectra show that excess flux (relative to a power-law continuum) in the soft X-ray band appears before the start of the anomalous emission-line behavior, peaks during the period of the anomaly, and then declines. This is a model-independent result suggesting that the soft excess is related to the anomaly. We divide the Swift data into on- and off-anomaly spectra to characterize the soft excess via spectral fitting. The cause of the spectral differences is likely due to a change in the intrinsic spectrum rather than to variable obscuration or partial covering. The Chandra spectra have lower signal-to-noise ratios, but are consistent with the Swift data. Our preferred model of the soft excess is emission from an optically thick, warm Comptonizing corona, the effective optical depth of which increases during the anomaly. This model simultaneously explains all three observations: the UV emission-line flux decrease, the soft-excess increase, and the emission-line anomaly.
Tumour stroma percentage (TSP) has previously been reported to predict survival in patients with colorectal cancer (CRC); however, whether this is independent of other aspects of the tumour ...microenvironment is unknown. In the present study, the relationship between TSP, the tumour microenvironment and survival was examined in patients undergoing elective, curative CRC resection.
Patients undergoing resection at a single centre (1997–2008) were identified from a prospective database. TSP was measured at the invasive margin and its association with cancer-specific survival (CSS) and clinicopathological characteristics examined.
Three hundred and thirty-one patients were included in the analysis. TSP was associated with CSS in patients with stage I–III disease hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.17–2.92, P = 0.009, independent of age, systemic inflammation, N stage, venous invasion and Klintrup–Mäkinen score. Furthermore, TSP was associated with reduced CSS in patients with node-negative disease (HR 2.14, 95% CI 1.01–4.54, P = 0.048) and those who received adjuvant chemotherapy (HR 2.83, 95% CI 1.23–6.53, P = 0.015), independent of venous invasion and host inflammatory responses. TSP was associated with several adverse pathological characteristics, including advanced T and N stage. Furthermore, TSP was associated with an infiltrative invasive margin and inversely associated with necrosis.
The TSP was a significant predictor of survival in patients undergoing elective, curative CRC resection, independent of adverse pathological characteristics and host inflammatory responses. In addition, TSP was strongly associated with local tumour growth and invasion.
Prostate cancer is initially androgen-dependent but, over time, usually develops hormone- and chemo-resistance. The present study investigated a role for p21-activated kinase 4 (PAK4) in prostate ...cancer progression. PAK4 activation was markedly inhibited by H89, a specific protein kinase A (PKA) inhibitor, and PAK4 was activated by the elevation of cAMP. The catalytic subunit of PKA interacted with the regulatory domain of PAK4, and directly phosphorylated PAK4 at serine 474 (S474). Catalytically active PAK4 enhanced the transcriptional activity of CREB independent of S133 phosphorylation. Stable knockdown of PAK4 in PC-3 and DU145 prostate cancer cells inhibited tumor formation in nude mice. Decreased tumorigenicity correlated with decreased expression of CREB and its targets, including Bcl-2 and cyclin A1. Additionally, in androgen-dependent LNCap-FGC cells, PAK4 regulated cAMP-induced neuroendocrine differentiation, which is known to promote tumor progression. Finally, PAK4 enhanced survival and decreased apoptosis following chemotherapy. These results suggested that PAK4 regulates progression toward hormone- and chemo-resistance in prostate cancer, and this study identified both a novel activation mechanism and potential downstream effector pathways. Therefore, PAK4 may be a promising therapeutic target in prostate cancer.
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