Aggressive cancers and embryonic stem (ES) cells share a common gene expression signature. Identifying the key factors/pathway(s) within this ES signature responsible for the aggressiveness of ...cancers can lead to a potential cure. In this study, we find that SALL4, a gene involved in the maintenance of ES cell self-renewal, is aberrantly expressed in 47.7% of primary human endometrial cancer samples. It is not expressed in normal or hyperplastic endometrial. More importantly, SALL4 expression is positively correlated with worse patient survival and aggressive features such as metastasis in endometrial carcinoma. Further functional studies have shown that loss of SALL4 inhibits endometrial cancer cell growth in vitro and tumorigenicity in vivo, as a result of inhibition of cell proliferation and increased apoptosis. In addition, downregulation of SALL4 significantly impedes the migration and invasion properties of endometrial cancer cells in vitro and their metastatic potential in vivo. Furthermore, manipulation of SALL4 expression can affect drug sensitivity of endometrial cancer cells to carboplatin. Moreover, we show that SALL4 specifically binds to the c-Myc promoter region in endometrial cancer cells. While downregulation of SALL4 leads to a decreased expression of c-Myc at both protein and mRNA levels, ectopic SALL4 overexpression causes increased c-Myc protein and mRNA expression, indicating that c-Myc is one of the SALL4 downstream targets in endometrial tumorigenesis. In summary, we are the first to demonstrate that SALL4 has functional role(s) in metastasis and drug resistance in aggressive endometrial cancer. As a consequence of its functional roles in cancer cell and absence in normal tissue, SALL4 is a potential novel therapeutic target for the high-risk endometrial cancer patient population.
In this paper, the spin and parity of the Zc(3900)± state are determined to be JP = 1+ with a statistical significance larger than 7σ over other quantum numbers in a partial wave analysis of the ...process e+e- → π+π-J/Ψ. We use a data sample of 1.92 fb-1 accumulated at $ \sqrt{s}=4.23 $ and 4.26 GeV with the BESIII experiment. When parametrizing the Zc(3900)± with a Flatté-like formula, we determine its pole mass Mpole = (3881.2±4.2stat ±52.7syst) MeV/c2 and pole width Γpole = (51.8± 4.6stat ± 36.0syst) MeV. Finally, we also measure cross sections for the process e+e- → Zc(3900)+π- + c.c. → J/Ψπ+π- and determine an upper limit at the 90% confidence level for the process e+e- → Zc(4020)+π- + c.c. → J/Ψ π+π-.
Ribociclib plus fulvestrant demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits in patients with hormone receptor-positive, human epidermal growth factor ...receptor 2-negative (HR+/HER2−) advanced breast cancer (ABC). Here we present a new landmark in survival follow-up for a phase III cyclin-dependent kinases 4 and 6 inhibitor clinical trial in patients with ABC (median, 56.3 months).
This phase III, randomized, double-blind, placebo-controlled trial was conducted at 174 sites (30 countries). Patients were men and postmenopausal women (age ≥18 years) with histologically/cytologically confirmed HR+/HER2− ABC. Patients could have received ≤1 line of endocrine therapy (ET) but no chemotherapy for ABC. Patients, assigned 2:1, were stratified by the presence/absence of liver/lung metastases and previous ET. Patients received intramuscular fulvestrant (500 mg, day 1 of each 28-day cycle plus day 15 of cycle 1) with oral ribociclib (600 mg/day, 3 weeks on, 1 week off) or placebo. Efficacy analyses were by intention to treat. Safety was assessed in patients receiving ≥1 dose study treatment. OS was a secondary endpoint. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615; no longer enrolling).
Between 18 June 2015 and 10 June 2016, 726 patients were randomly assigned (484, ribociclib; 242, placebo). At data cut-off (30 October 2020), median OS (mOS) was 53.7 months (ribociclib) versus 41.5 months (placebo) hazard ratio (HR), 0.73; 95% confidence interval (CI) 0.59-0.90. Subgroup analyses were consistent with overall population. In the first-line setting, most patients in the ribociclib arm (∼60%) lived longer than median follow-up; mOS was 51.8 months in the placebo arm (HR, 0.64; 95% CI 0.46-0.88). In the second-line setting, mOS was 39.7 months (ribociclib) versus 33.7 months (placebo) (HR, 0.78; 95% CI 0.59-1.04). No apparent drug–drug interaction between ribociclib and fulvestrant or new safety signals were observed.
This analysis reported extended OS follow-up in MONALEESA-3. mOS was ∼12 months longer in patients with HR+/HER2− ABC treated with ribociclib plus fulvestrant compared with fulvestrant monotherapy.
•We report an extended OS follow-up to the MONALEESA-3 trial (median, 56.3 months).•mOS was longer for the ribociclib arm versus the placebo arm: 53.7 versus 41.5 months (HR, 0.73; 95% CI 0.59-0.90).•OS benefit was observed with ribociclib in the first- and second-line settings.•No apparent drug–drug interaction between ribociclib and fulvestrant or new safety signals were observed.
Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the ...potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts’ personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.
A FeFe-hydrogenase model (1) containing a chelating diphosphine ligand with a pendant amine was readily oxidized by Fc+ (Fc = Cp2Fe) to a FeIIFeI complex (1+), which was isolated at room temperature. ...The structure of 1+ with a semibridging CO and a vacant apical site was determined by X-ray crystallography. Complex 1+ catalytically activates H2 at 1 atm at 25 °C in the presence of excess Fc+ and P(o-tol)3. More interestingly, the catalytic activity of 1+ for H2 oxidation remains unchanged in the presence of ca. 2% CO. A computational study of the reaction mechanism showed that the most favorable activation free energy involves a rotation of the bridging CO to an apical position followed by activation of H2 with the help of the internal amine to give a bridging hydride intermediate.
Purpose
A causal biomarker for acute respiratory distress syndrome (ARDS) could fuel precision therapy options. Plasma angiopoietin-2 (ANG2), a vascular permeability marker, is a strong candidate on ...the basis of experimental and observational evidence. We used genetic causal inference methods—Mendelian randomization and mediation—to infer potential effects of plasma ANG2.
Methods
We genotyped 703 septic subjects, measured ICU admission plasma ANG2, and performed a quantitative trait loci (QTL) analysis to determine variants in the
ANGPT2
gene associated with plasma ANG2 (
p
< 0.005). We then used linear regression and post-estimation analysis to genetically predict plasma ANG2 and tested genetically predicted ANG2 for ARDS association using logistic regression. We estimated the proportion of the genetic effect explained by plasma ANG2 using mediation analysis.
Results
Plasma ANG2 was strongly associated with ARDS (OR 1.59 (95% CI 1.35, 1.88) per log). Five
ANGPT2
variants were associated with ANG2 in European ancestry subjects (
n
= 404). Rs2442608C, the most extreme
cis
QTL (coefficient 0.22, 95% CI 0.09–0.36,
p
= 0.001), was associated with higher ARDS risk: adjusted OR 1.38 (95% CI 1.01, 1.87)
, p
= 0.042. No significant QTL were identified in African ancestry subjects. Genetically predicted plasma ANG2 was associated with ARDS risk: adjusted OR 2.25 (95% CI 1.06–4.78),
p
= 0.035. Plasma ANG2 mediated 34% of the rs2442608C-related ARDS risk.
Conclusions
In septic European ancestry subjects, the strongest ANG2-determining
ANGPT2
genetic variant is associated with higher ARDS risk. Plasma ANG2 may be a causal factor in ARDS development. Strategies to reduce plasma ANG2 warrant testing to prevent or treat sepsis-associated ARDS.
Using a data sample corresponding to an integrated luminosity of 2.93 fb−1 taken at a center-of-mass energy of 3.773 GeV with the BESIII detector operated at the BEPCII collider, we perform an ...analysis of the semileptonic decays D0(+)→π−(0)μ+νμ. The branching fractions of D0→π−μ+νμ and D+→π0μ+νμ are measured to be (0.272±0.008stat±0.006syst)% and (0.350±0.011stat±0.010syst)%, respectively, where the former is of much improved precision compared to previous results and the latter is determined for the first time. Using these results along with previous BESIII measurements of D0(+)→π−(0)e+νe, we calculate the branching fraction ratios to be R0≡BD0→π−μ+νμ/BD0→π−e+νe=0.922±0.030stat±0.022syst and R+≡BD+→π0μ+νμ/BD+→π0e+νe=0.964±0.037stat±0.026syst, which are compatible with the theoretical expectation of lepton flavor universality within 1.7σ and 0.5σ, respectively. We also examine the branching fraction ratios in different four-momentum transfer square regions, and find no significant deviations from the standard model predictions.
A solution culture experiment was conducted to investigate the effect of silicate on the yield and arsenate uptake by rice. Rice seedlings (Oryza sativa L. cv. Weiyou 77) were cultured in modified ...Hoagland nutrient solution containing three arsenate levels (0, 0.5 and 1.0 mg L⁻¹ As) and four silicate levels (0, 14, 28 and 56 mg L⁻¹ Si). Addition of Si significantly increased shoot dry weight (P = 0.001) but had little effect on root dry weight (P = 0.43). Addition of As had no significant effect on shoot dry weight (P = 0.43) but significantly increased root dry weight (P = 0.01). Silicon concentrations in shoots and roots increased proportionally to increasing amounts of externally supplied Si (P < 0.001). The presence of As in the nutrient solution had little effect on shoot Si concentration (P = 0.16) but significantly decreased root Si concentration (P = 0.005). Increasing external Si concentration significantly decreased shoot and root As concentrations and total As uptake by rice seedlings (P < 0.001). In addition, Si significantly decreased shoot P concentration and shoot P uptake (P < 0.001). The data clearly demonstrate a beneficial effect of Si on the growth of rice seedlings. Addition of Si to the growth medium also inhibited the uptake of arsenate and phosphate by the rice seedlings.
Close white dwarf binaries consisting of a white dwarf and an A-, F-, G-, or K-type main-sequence star, henceforth close WD+AFGK binaries, are ideal systems to understand the nature of type Ia ...supernovae progenitors and to test binary evolution models. In this work we identify 775 WD+AFGK candidates from TGAS (The Tycho-Gaia Astrometric Solution) and Gaia Data Release 2 (DR2), a well-defined sample of stars with available parallaxes, and we measure radial velocities (RVs) for 275 of them with the aim of identifying close binaries. The RVs have been measured from high-resolution spectra obtained at the Xinglong 2.16 m Telescope and the San Pedro Mártir 2.12 m Telescope and/or from available LAMOST DR6 (low-resolution) and RAVE DR5 (medium-resolution) spectra. We identify 23 WD+AFGK systems displaying more than 3 RV variation among 151 systems for which the measured values are obtained from different nights. Our WD+AFGK binary sample contains both AFGK dwarfs and giants, with a giant fraction ∼43%. The close binary fractions we determine for the WD+AFGK dwarf and giant samples are 24% and 15%, respectively. We also determine the stellar parameters (i.e., effective temperature, surface gravity, metallicity, mass, and radius) of the AFGK companions with available high-resolution spectra. The stellar parameter distributions of the AFGK companions that are members of close and wide binary candidates do not show statistically significant differences.
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