Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options
. Lenvatinib is a small-molecule inhibitor of multiple receptor ...tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit
. Here, using a kinome-centred CRISPR-Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer. The combination of the EGFR inhibitor gefitinib and lenvatinib displays potent anti-proliferative effects in vitro in liver cancer cell lines that express EGFR and in vivo in xenografted liver cancer cell lines, immunocompetent mouse models and patient-derived HCC tumours in mice. Mechanistically, inhibition of fibroblast growth factor receptor (FGFR) by lenvatinib treatment leads to feedback activation of the EGFR-PAK2-ERK5 signalling axis, which is blocked by EGFR inhibition. Treatment of 12 patients with advanced HCC who were unresponsive to lenvatinib treatment with the combination of lenvatinib plus gefitinib (trial identifier NCT04642547) resulted in meaningful clinical responses. The combination therapy identified here may represent a promising strategy for the approximately 50% of patients with advanced HCC who have high levels of EGFR.
Vegetation moisture content is an important early indicator of forest drought stress, disease and fire risk. Existing remote sensing techniques to measure biochemical properties of vegetation, such ...as Equivalent Water Thickness (EWT), are limited by an inability to differentiate canopy and understorey properties and are influenced by variations in canopy structure. By providing a range-resolved estimate of reflectance, laser scanner measurements have the potential to overcome these limitations. Dual-wavelength laser scanning can provide an active measurement of reflectance from which spectral indices can be derived that are insensitive to range, incidence angle and scattering area of the target within the laser beam, factors that make exploiting single-wavelength laser scanner intensity data difficult.
This study demonstrates the potential of dual-wavelength laser scanning for measurement of leaf biochemical properties, through determining the relationship between a laser-scanner-derived spectral index, using near infrared (1063nm) and middle infrared (1545nm) wavelengths, and the EWT of individual leaves. The suitability and sensitivity of the index is tested using a leaf optical properties model (PROSPECT-5) and the method is tested experimentally under laboratory conditions using the Salford Advanced Laser Canopy Analyser. A strong relationship (R2=0.8, RMSE=0.0069gcm−2) was found between a normalised ratio of the two wavelengths and measured EWT of leaf samples. The relationship corresponds well to that predicted by modelling. However, the experimental data also revealed significant spatial variability in the index value across individual leaves, suggesting heterogeneity in moisture distribution at within-leaf scales. The study suggests significant potential for using dual-wavelength and multispectral laser scanning for measuring vegetation biochemical properties.
► Dual-wavelength LiDAR shows potential to improve estimates of canopy biochemistry. ► A Laser-derived spectral index is strongly related to leaf Equivalent Water Thickness. ► Experimental results match those predicted by leaf reflectance modelling. ► An application of the Salford Advanced Laser Canopy Analyser is demonstrated.
Myeloid cells are abundant and plastic immune cell subsets in the liver, to which pro-tumorigenic, inflammatory and immunosuppressive roles have been assigned in the course of tumorigenesis. Yet ...several aspects underlying their dynamic alterations in hepatocellular carcinoma (HCC) progression remain elusive, including the impact of distinct genetic mutations in shaping a cancer-permissive tumor microenvironment (TME). Here, in newly generated, clinically-relevant somatic female HCC mouse models, we identify cancer genetics' specific and stage-dependent alterations of the liver TME associated with distinct histopathological and malignant HCC features. Mitogen-activated protein kinase (MAPK)-activated, Nras
-driven tumors exhibit a mixed phenotype of prominent inflammation and immunosuppression in a T cell-excluded TME. Mechanistically, we report a Nras
cancer cell-driven, MEK-ERK1/2-SP1-dependent GM-CSF secretion enabling the accumulation of immunosuppressive and proinflammatory monocyte-derived Ly6C
cells. GM-CSF blockade curbs the accumulation of these cells, reduces inflammation, induces cancer cell death and prolongs animal survival. Furthermore, GM-CSF neutralization synergizes with a vascular endothelial growth factor (VEGF) inhibitor to restrain HCC outgrowth. These findings underscore the profound alterations of the myeloid TME consequential to MAPK pathway activation intensity and the potential of GM-CSF inhibition as a myeloid-centric therapy tailored to subsets of HCC patients.
Preclinical studies have demonstrated that high mechanical index (MI) impulses from a diagnostic ultrasound transducer during an intravenous microbubble infusion (sonothrombolysis) can restore ...epicardial and microvascular flow in acute ST-segment elevation myocardial infarction (STEMI).
This study tested the clinical effectiveness of sonothrombolysis in patients with STEMI.
Patients with their first STEMI were prospectively randomized to either diagnostic ultrasound–guided high MI impulses during an intravenous Definity (Lantheus Medical Imaging, North Billerica, Massachusetts) infusion before, and following, emergent percutaneous coronary intervention (PCI), or to a control group that received PCI only (n = 50 in each group). A reference first STEMI group (n = 203) who arrived outside the randomization window was also analyzed. Angiographic recanalization before PCI, ST-segment resolution, infarct size by magnetic resonance imaging, and systolic function (LVEF) at 6 months were compared.
ST-segment resolution occurred in 16 (32%) high MI PCI versus 2 (4%) PCI-only patients before PCI, and angiographic recanalization was 48% in high MI/PCI versus 20% in PCI only and 21% in the reference group (p < 0.001). Infarct size was reduced (29 ± 22 g high MI/PCI vs. 40 ± 20 g PCI only; p = 0.026). LVEF was not different between groups before treatment (44 ± 11% vs. 43 ± 10%), but increased immediately after PCI in the high MI/PCI group (p = 0.03), and remained higher at 6 months (p = 0.015). Need for implantable defibrillator (LVEF ≤30%) was reduced in the high MI/PCI group (5% vs. 18% PCI only; p = 0.045).
Sonothrombolysis added to PCI improves recanalization rates and reduces infarct size, resulting in sustained improvements in systolic function after STEMI. (Therapeutic Use of Ultrasound in Acute Coronary Artery Disease; NCT02410330).
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Stars in open clusters are expected to share an identical abundance pattern. Establishing the level of chemical homogeneity in a given open cluster deserves further study as it is the basis of the ...concept of chemical tagging to unravel the history of the Milky Way. M67 is particularly interesting given its solar metallicity and age as well as being a dense cluster environment. We conducted a strictly line-by-line differential chemical abundance analysis of two solar twins in M67: M67-1194 and M67-1315. Stellar atmospheric parameters and elemental abundances were obtained with high precision using Keck/High Resolution Echelle Spectrometer spectra. M67-1194 is essentially identical to the Sun in terms of its stellar parameters. M67-1315 is warmer than M67-1194 by ≈150 K as well as slightly more metal-poor than M67-1194 by ≈0.05 dex. M67-1194 is also found to have identical chemical composition to the Sun, confirming its solar-twin nature. The abundance ratios X/Fe of M67-1315 are similar to the solar abundances for elements with atomic number Z ≤ 30, while most neutron-capture elements are enriched by ≈0.05 dex, which might be attributed to enrichment from a mixture of asymptotic giant branch ejecta and r-process material. The distinct chemical abundances for the neutron-capture elements in M67-1315 and the lower metallicity of this star compared to M67-1194, indicate that the stars in M67 are likely not chemically homogeneous. This poses a challenge for the concept of chemical tagging since it is based on the assumption of stars forming in the same star-forming aggregate.
Activated immune cells are insulin sensitive and utilize copious amounts of glucose. Because chromium (Cr) increases insulin sensitivity and may be immunomodulatory, our objective was to evaluate the ...effect of supplemental Cr (KemTrace Cr propionate, 20 g/d; Kemin Industries Inc., Des Moines, IA) on immune system glucose utilization and immune system dynamics following an intravenous endotoxin challenge in lactating Holstein cows. Twenty cows (320 ± 18 d in milk) were randomly assigned to 1 of 4 treatments: (1) pair-fed (PF) control (PF-CON; 5 mL of saline; n = 5), (2) PF and Cr supplemented (PF-Cr; 5 mL of saline; n = 5), (3) lipopolysaccharide (LPS)-euglycemic clamp and control supplemented (LPS-CON; 0.375 µg/kg of body weight LPS; n = 5), and (4) LPS-euglycemic clamp and Cr supplemented (LPS-Cr; 0.375 µg/kg of body weight LPS; n = 5). The experiment was conducted serially in 3 periods (P). During P1 (3 d), cows received their respective dietary treatments and baseline values were obtained. At the initiation of P2 (2 d), either a 12-h LPS-euglycemic clamp was conducted or cows were PF to their respective dietary counterparts. During P3 (3 d), cows consumed feed ad libitum and continued to receive their respective dietary treatment. During P2, LPS administration decreased dry matter intake (DMI; 40%) similarly among diets, and by experimental design the pattern and magnitude of reduced DMI were similar in the PF cohorts. During P3, LPS-Cr cows tended to have decreased DMI (6%) relative to LPS-CON cows. Relative to controls, milk yield from LPS-challenged cows decreased (58%) during P2 and LPS-Cr cows produced less (16%) milk than LPS-CON cows. During P3, milk yield progressively increased similarly in LPS-administered cows, but overall milk yield remained decreased (24%) compared with PF controls. There were no dietary treatment differences in milk yield during P3. Circulating insulin increased 9- and 15-fold in LPS-administered cows at 6 and 12 h postbolus, respectively, compared with PF controls. Compared with LPS-CON cows, circulating insulin in LPS-Cr cows was decreased (48%) at 6 h postbolus. Relative to PF cows, circulating LPS binding protein and serum amyloid A from LPS-administered cows increased 2- and 5-fold, respectively. Compared with PF cows, blood neutrophil counts in LPS-infused cows initially decreased, then gradually increased 163%. Between 18 and 48 h postbolus, the number of neutrophils was increased (12%) in LPS-Cr versus LPS-CON cows. The 12-h total glucose deficit was 220 and 1,777 g for the PF and LPS treatments, respectively, but glucose utilization following immune activation was not influenced by Cr. In summary, supplemental Cr reduced the insulin response and increased circulating neutrophils following an LPS challenge but did not appear to alter the immune system's glucose requirement following acute and intense activation.
Plant domestication was a pivotal accomplishment in human history, but also led to a reduction in genetic diversity of crop species compared to their wild ancestors. How this reduced genetic ...diversity affected plant-microbe interactions belowground is largely unknown. Here, we investigated the genetic relatedness, root phenotypic traits and rhizobacterial community composition of modern and wild accessions of common bean (Phaseolus vulgaris) grown in agricultural soil from the highlands of Colombia, one of the centers of common bean diversification. Diversity Array Technology-based genotyping and phenotyping of local common bean accessions showed significant genetic and root architectural differences between wild and modern accessions, with a higher specific root length for the wild accessions. Canonical Correspondence Analysis indicated that the divergence in rhizobacterial community composition between wild and modern bean accessions is associated with differences in specific root length. Along the bean genotypic trajectory, going from wild to modern, we observed a gradual decrease in relative abundance of Bacteroidetes, mainly Chitinophagaceae and Cytophagaceae, and an increase in relative abundance of Actinobacteria and Proteobacteria, in particular Nocardioidaceae and Rhizobiaceae, respectively. Collectively, these results establish a link between common bean domestication, specific root morphological traits and rhizobacterial community assembly.
Although both frailty and low vitamin D have been separately associated with an increased risk for adverse health, their joined effects on mortality have not been reported. The current study examined ...prospectively the effects of frailty and vitamin D status on mortality in US older adults.
Participants aged ≥ 60 years in The Third National Health and Nutrition Examination Survey with 12 years of mortality follow-up were included in the analysis (n=4731). Frailty was defined as meeting three or more criteria and pre-frailty as meeting one or two of the five frailty criteria (low body mass index (BMI), slow walking, weakness, exhaustion and low physical activity). Vitamin D status was assessed by serum 25-hydroxyvitamin D (25(OH)D) and categorized into quartiles. Analyses were adjusted for gender, race, age, smoking, education, latitude and other comorbid conditions.
Serum 25(OH)D concentrations were lowest in participants with frailty, intermediate in participants with pre-frailty and highest in participants without frailty. The odds of frailty in the lowest quartile of serum 25(OH)D was 1.94 times the odds in the highest quartile (95% confidence interval (CI): 1.09-3.44). Mortality was positively associated with frailty, with the risk among participants who were frail and had low serum 25(OH)D being significantly higher than those who were not frail and who had high concentrations of serum 25(OH)D (hazards ratio 2.98; 95% CI: 2.01-4.42).
Our results suggest that low serum 25(OH)D is associated with frailty, and there is additive joint effects of serum 25(OH)D and frailty on all-cause mortality in older adults.
The relationship between macronutrients and cardiovascular disease and mortality is controversial. Most available data are from European and North American populations where nutrition excess is more ...likely, so their applicability to other populations is unclear.
The Prospective Urban Rural Epidemiology (PURE) study is a large, epidemiological cohort study of individuals aged 35–70 years (enrolled between Jan 1, 2003, and March 31, 2013) in 18 countries with a median follow-up of 7·4 years (IQR 5·3–9·3). Dietary intake of 135 335 individuals was recorded using validated food frequency questionnaires. The primary outcomes were total mortality and major cardiovascular events (fatal cardiovascular disease, non-fatal myocardial infarction, stroke, and heart failure). Secondary outcomes were all myocardial infarctions, stroke, cardiovascular disease mortality, and non-cardiovascular disease mortality. Participants were categorised into quintiles of nutrient intake (carbohydrate, fats, and protein) based on percentage of energy provided by nutrients. We assessed the associations between consumption of carbohydrate, total fat, and each type of fat with cardiovascular disease and total mortality. We calculated hazard ratios (HRs) using a multivariable Cox frailty model with random intercepts to account for centre clustering.
During follow-up, we documented 5796 deaths and 4784 major cardiovascular disease events. Higher carbohydrate intake was associated with an increased risk of total mortality (highest quintile 5 vs lowest quintile quintile 1 category, HR 1·28 95% CI 1·12–1·46, ptrend=0·0001) but not with the risk of cardiovascular disease or cardiovascular disease mortality. Intake of total fat and each type of fat was associated with lower risk of total mortality (quintile 5 vs quintile 1, total fat: HR 0·77 95% CI 0·67–0·87, ptrend<0·0001; saturated fat, HR 0·86 0·76–0·99, ptrend=0·0088; monounsaturated fat: HR 0·81 0·71–0·92, ptrend<0·0001; and polyunsaturated fat: HR 0·80 0·71–0·89, ptrend<0·0001). Higher saturated fat intake was associated with lower risk of stroke (quintile 5 vs quintile 1, HR 0·79 95% CI 0·64–0·98, ptrend=0·0498). Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality.
High carbohydrate intake was associated with higher risk of total mortality, whereas total fat and individual types of fat were related to lower total mortality. Total fat and types of fat were not associated with cardiovascular disease, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke. Global dietary guidelines should be reconsidered in light of these findings.
Full funding sources listed at the end of the paper (see Acknowledgments).
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•High entropy alloys produced by mechanical alloying formed solid solutions.•The alloys in milled state presented BCC structures as main one, except AlCoFeNi.•Zinc addition favored ...the microstructural refinement of high entropy alloys.•The combination of multiple alloying elements favored the alloys hardening.
High entropy alloys were designed from equiatomic multicomponent systems using powder metallurgy including mechanical alloying and sintering. The structure and morphology of the resulting alloys were characterized by means of X-ray diffraction, scanning electron microscopy, transmission electron microscopy techniques and their hardness values were also determined in the Vickers scale. The results indicate under the milling conditions used, the AlCoFeNiZn, AlCoFeNiMoTi and AlCoFeNiMoTiZn alloys crystallized forming BCC structures whereas the AlCoFeNi alloy presented two different phases, one with FCC structure and the other one with BCC. The synthesis method resulted in alloys with grain sizes in the nano scale having values between 4.1 and 9.4 nm on the powder form up to 40.1 nm after sintering phenomenon which lead to phase transformations which were more evident in the Mo-containing alloys. In addition, the AlCoFeNiZn and AlCoFeNiMoTiZn alloys did not show Zn traces after sintering as it was suggested by chemical analyses using energy dispersive spectroscopy, suggesting it is lost by evaporation during sintering process. Mo-containing systems exhibited the highest microhardness in both milled and sintered conditions.
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