In metastatic urothelial carcinoma (mUC), predictive biomarkers that correlate with response to immune checkpoint inhibitors (ICIs) are lacking. Here, we interrogated genomic and clinical features ...associated with response to ICIs in mUC.
Sixty two mUC patients treated with ICI who had targeted tumour sequencing were studied. We examined associations between candidate biomarkers and clinical benefit (CB, any objective reduction in tumour size) versus no clinical benefit (NCB, no change or objective increase in tumour size). Both univariable and multivariable analyses for associations were conducted. A comparator cohort of 39 mUC patients treated with taxanes was analysed by using the same methodology.
Nine clinical and seven genomic factors correlated with clinical outcomes in univariable analysis in the ICI cohort. Among the 16 factors, neutrophil-to-lymphocyte ratio (NLR) ≥5 (OR = 0.12, 95% CI, 0.01-1.15), visceral metastasis (OR = 0.05, 95% CI, 0.01-0.43) and single-nucleotide variant (SNV) count < 10 (OR = 0.04, 95% CI, 0.006-0.27) were identified as independent predictors of NCB to ICI in multivariable analysis (c-statistic = 0.90). None of the 16 variables were associated with clinical benefit in the taxane cohort.
This three-factor model includes genomic (SNV count >9) and clinical (NLR <5, lack of visceral metastasis) variables predictive for benefit to ICI but not taxane therapy for mUC. External validation of these hypothesis-generating results is warranted to enable use in routine clinical care.
Summary
Inconsistent findings in regard to association between thiazide diuretic use and the risk of fracture have been reported during the past decade. This updated meta-analysis, which pooled data ...from 11 qualified prospective designed studies, found that thiazides have a significant protective effect on fracture risk.
Introduction
An updated comprehensive meta-analysis examine the association between thiazide diuretic use and therisk of fracture is needed.
Methods
Cohort studies regarding thiazide diuretic exposure and the risk of fracture, published from inception to May 1 2017, were identified through MEDLINE, EMBASE, SCOPUS, and the Cochrane Database of Systematic Reviews. The literature search, study selection, study appraisal, and data extraction were pre-defined in the protocol and were independently conducted by two investigators. Due to the heterogeneity of the original studies, a random effects model was used to pool the confounder-adjusted relative risk (RR).
Results
Eleven eligible cohort studies involving 2,193,160 participants were included for analysis. Overall, thiazide diuretic users, as compared with non-users, had a significant 14% reduction in the risk of all fractures (relative risk RR, 0.86; 95% confidence interval CI, 0.80–0.93;
p
= 0.009) and an 18% reduction in the risk of hip fracture (RR, 0.82; 95%CI, 0.80–0.93;
p
= 0.009). However, the effect size associated with thiazide use became slightly weaker when the analysis was limited to only high-quality original studies (quality score > 8) (RR, 0.89; 95%CI, 0.80–0.99;
p
= 0.005), studies with a larger sample size (> 10,000) (RR, 0.90; 95%CI, 0.80–1.00;
p
= 0.002), and studies published after 2007 (RR, 0.92; 95%CI, 0.82–1.02;
p
= 0.001).
Conclusion
Our findings indicate that thiazide diuretic use may convey a decreased risk of fracture and as such, the protective effect of this class of medicine should be considered when prescribing thiazide diuretics in clinical practice.
Cabozantinib is approved for the first and subsequent line treatment of metastatic clear-cell renal cell carcinoma (ccRCC) based on trials in which most patients were immune checkpoint blockade (ICB) ...naive. With an expanding role of ICB in earlier lines of therapy, we assessed activity of cabozantinib in patients with metastatic ccRCC after progressing on anti-PD-1/PD-L1–based ICBs.
We retrospectively analysed the clinical outcomes of 86 patients from 2 academic centres who received cabozantinib after progression on ICB alone, ICB in combination with vascular endothelial growth factor inhibitors (VEGFis) or ICB in combination with other therapies. Overall response rate (ORR, investigator assessed), time to treatment failure (TTF), overall survival (OS) and toxicities leading to dose reductions or cessation were evaluated.
Eighty-six patients were included in the analysis; the median age was 63 years (range 33–84) and the median number of prior therapies was 2 (range 1–10). The type of prior ICB therapy was ICBs alone (64%), an ICB in combination with a VEGFi (29%) or ICBs in combination with other therapies (7%). At the time of cabozantinib treatment, 71% of patients were in the International Metastatic RCC Database Consortium good- or intermediate-risk groups. Approximately half of patients (52%) were started on cabozantinib at the full 60 mg daily dose. The ORR was 36% (95% confidence interval CI = 26–47%) with no complete response and 43% achieving stable disease; 21% had primary progressive disease. The median TTF was 6.5 months (95% CI = 5.3–8.5.). The median OS was 13.1 months (95% CI = 8.7-NR) with 55% (95% CI = 41–66%) OS rate at 12 months. Most common reasons for dose reductions were fatigue (27%), palmar-plantar erythrodysesthesia (16%) and diarrhoea (10%).
Cabozantinib is active in patients treated with prior ICB-based therapies, with no new safety signals. This study supports the use of cabozantinib after ICB-based therapies.
•Retrospective analysis of 86 patients receiving cabozantinib after immunotherapy.•Sixty-four percent received immunotherapy alone and 29% received in combination with vascular endothelial growth factors.•The overall response rate was 36% (95% confidence interval = 26–47%); the median overall survival was 13 months.•The toxicity profile was similar to what was reported in the METEOR trial.•Cabozantinib is active after immunotherapy with no new safety signals.
Out-of-plane ferroelectricity with a high transition temperature in nanometer-scale films is required to miniaturize electronic devices. Direct visualization of stable ferroelectric polarization and ...its switching behavior in atomically thick films is critical for achieving this goal. Here, ferroelectric order at room temperature in the two-dimensional limit is demonstrated in tetragonal BiFeO
ultrathin films. Using aberration-corrected scanning transmission electron microscopy, we directly observed robust out-of-plane spontaneous polarization in one-unit-cell-thick BiFeO
films. High-resolution piezoresponse force microscopy measurements show that the polarization is stable and switchable, whereas a tunneling electroresistance effect of up to 370% is achieved in BiFeO
films. Based on first-principles calculations and Kelvin probe force microscopy measurements, we explain the mechanism of polarization stabilization by the ionic displacements in oxide electrode and the surface charges. Our results indicate that critical thickness for ferroelectricity in the BiFeO
film is virtually absent, making it a promising candidate for high-density nonvolatile memories.
Abstract Introduction The laminin α4 subunit (LAMA4) has been shown to promote migration, proliferation, and survival of various cell types. This study investigated LAMA4's role in trophoblast cells ...during placental development. Methods LAMA4 expression was immunohistochemically assessed in the first trimester and term human placentas. LAMA4 siRNA was applied to silence LAMA4 expression in extravillous explants and HTR8/SVneo cells. Hypoxia–reoxygenation (H/R) conditions were applied to mimic preeclampsia. LAMA4 expression and trophoblast cell invasion, migration, and tube formation (a measure of angiogenesis) were assessed in HTR8/SVneo cells. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 was used to study the mechanism underlying LAMA4 activity. LAMA4 promoter methylation was assessed by bisulfite-sequencing polymerase chain reaction (PCR) or methylation-specific PCR. Results LAMA4 levels in preeclamptic placentas were significantly lower than those in controls. LAMA4 silencing significantly inhibited extravillous explant outgrowth as well as HTR8/SVneo cell invasion and migration. H/R conditions significantly lowered LAMA4 expression. Application of either H/R conditions or LAMA4 silencing both significantly decreased HTR8/SVneo cell invasion, migration, and tube formation, decreased MMP2 and MMP9 expression, and increased TIMP2 expression. SB203580 significantly reduced LAMA4 expression. LAMA4 silencing significantly decreased p-p38, p-c-Jun N-terminal kinase (JNK), and p-extracellular signal-regulated kinase (ERK) expressions; by contrast, H/R conditions induced significant upregulation of p-p38 and p-ERK but decreased p-JNK. LAMA4 promoter methylation was not significantly altered in preeclamptic placentas compared to controls. Conclusions LAMA4 expression is lowered in preeclamptic placentas and promotes trophoblast cell invasion, migration, and angiogenesis. H/R conditions decrease LAMA4 expression and appear to decouple the positive relationship between LAMA4 expression and p38 and ERK activation.
Summary
Genetic risk of low BMD in African American women remains unclear. Based on SNPs discovered from a predominantly Caucasian sample, genetic profile was summarized and was found to be ...significantly associated with BMD variation in African American women.
Introduction
Osteoporosis is largely under-recognized and undertreated in African-American women, the post-fracture morbidity and mortality rates in this racial group is rather high. Since BMD was proved to be highly heritable, based on a comprehensive genome-wide meta-analysis that reported 63 BMD-related single nucleotide polymorphisms (SNPs), we aim to unravel the overall genetic risk for decreased BMD and osteoporosis in African-American women.
Methods
Genotype data of 842 African American women in a Women’s Health Initiative cohort were analyzed. Comprehensive genotype imputation was conducted at the Sanger Imputation Server. Multi-locus genetic risk scores (GRSs) based on 62 BMD-related single-nucleotide polymorphisms (SNPs) were calculated. The association between GRS and BMD was assessed by regression analysis. Longitudinal data was further analyzed using a generalized estimating equation, which helps achieve more efficient and unbiased regression parameters by accounting for the within-subject correlation of responses on dependent variables.
Results
After adjusting for age, body weight, hormone use, and previous fracture, for every unit increase of GRS.FN and GRS.LS, BMD at hip and lumbar spine decreased 0.124 g/cm
2
and 0.086 g/cm
2
, respectively. Collectively, the model accounted for 34.95% of the femoral neck BMD variation and 25.79% of lumbar spine BMD variation. Notably, GRS.FN and GRS.LS accounted for 2.03% and 2.39% of the total explained variance, respectively. The proportion of BMD variation can be explained by GRSs increasing as participants aged.
Conclusions
Genetic risk score was significantly associated with lower BMD in the current study, suggesting that SNPs discovered from prior meta-analysis based on primarily Caucasian population can also explain a considerable proportion of BMD variation in African Americans.
We present a protected superconducting qubit based on an effective circuit element that only allows pairs of Cooper pairs to tunnel. These dynamics give rise to a nearly degenerate ground state ...manifold indexed by the parity of tunneled Cooper pairs. We show that, when the circuit element is shunted by a large capacitance, this manifold can be used as a logical qubit that we expect to be insensitive to multiple relaxation and dephasing mechanisms.
For solving a class of complex symmetric linear systems, we introduce a new single-step iteration method, which can be taken as a fixed-point iteration adding the asymptotical error (FPAE). In order ...to accelerate the convergence, we further develop the parameterized variant of the FPAE (PFPAE) iteration method. Each iteration of the FPAE and the PFPAE methods requires the solution of only one linear system with a real symmetric positive definite coefficient matrix. Under suitable conditions, we derive the spectral radius of the FPAE and the PFPAE iteration matrices, and discuss the quasi-optimal parameters which minimize the above spectral radius. Numerical tests support the contention that the PFPAE iteration method has comparable advantage over some other commonly used iteration methods, particularly when the experimental optimal parameters are not used.
RSK1, an essential cellular kinase for Kaposi's sarcoma-associated herpesvirus (KSHV) replication, is highly phosphorylated and SUMOylated during KSHV lytic cycle, which determine the substrate ...phosphorylation and specificity of RSK1, respectively. However, the SUMO E3 ligase responsible for attaching SUMO to RSK1 has not yet been identified. By genome-wide screening, we found that KSHV ORF45 is necessary and sufficient to enhance RSK1 SUMOylation. Mechanistically, KSHV ORF45 binds to SUMOs via two classic SUMO-interacting motifs (SIMs) and functions as a SIM-dependent SUMO E3 ligase for RSK1. Mutations on these ORF45 SIMs resulted in much lower lytic gene expressions, viral DNA replication, and mature progeny virus production. Interestingly, KSHV ORF45 controls RSK1 SUMOylation and phosphorylation via two separated functional regions: SIMs and amino acid 17-90, respectively, which do not affect each other. Similar to KSHV ORF45, ORF45 of Rhesus Macaque Rhadinovirus has only one SIM and also increases RSK1 SUMOylation in a SIM-dependent manner, while other ORF45 homologues do not have this function. Our work characterized ORF45 as a novel virus encoded SUMO E3 ligase, which is required for ORF45-RSK1 axis-mediated KSHV lytic gene expression.
Paddy rice in monsoon Asia plays an important role in global food security and climate change. Here we documented annual dynamics of paddy rice areas in the northern frontier of Asia, including ...northeastern (NE) China, North Korea, South Korea, and Japan, from 2000 to 2014 through analysis of satellite images. The paddy rice area has increased by 120% (2.5 to 5.5 million ha) in NE China, in comparison to a decrease in South Korea and Japan, and the paddy rice centroid shifted northward from 41.16°N to 43.70°N (~310 km) in this period. Market, technology, policy, and climate together drove the rice expansion in NE China. The increased use of greenhouse nurseries, improved rice cultivars, agricultural subsidy policy, and a rising rice price generally promoted northward paddy rice expansion. The potential effects of large rice expansion on climate change and ecosystem services should be paid more attention to in the future.
Key Points
Paddy rice rapidly expanded northward in northeastern (NE) Asia from 2000 to 2014
Paddy rice in NE China expanded by 120% and dominated rice shift patterns in NE Asia
Market, technology, policy, and climate together drove rice expansion in NE China
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