Data_Sheet_1_ZAT10 plays dual roles in cadmium uptake and detoxification in Arabidopsis.pdf

Cadmium (Cd) is a harmful heavy metal that is risky for plant growth and human health. The zinc-finger transcription factor ZAT10 is highly conserved with ZAT6 and ZAT12, which are involved in Cd tolerance in plants. However, the definite function of ZAT10 in Cd tolerance remains uncertain. Here, we demonstrated that ZAT10 negatively regulated Cd uptake and enhanced Cd detoxification in Arabidopsis. The expression of ZAT10 in plants is induced by Cd treatment. The zat10 mutant plants exhibited a greater sensitivity to Cd stress and accumulated more Cd in both shoot and root. Further investigations revealed that ZAT10 repressed the transcriptional activity of IRT1, which encodes a key metal transporter involved in Cd uptake. Meanwhile, ZAT10 positively regulated four heavy metal detoxification-related genes: NAS1, NAS2, IRT2, and MTP3. We further found that ZAT10 interacts with FIT, but their regulatory relationship is still unclear. In addition, ZAT10 directly bound to its own promoter and repressed its transcription as a negative feedback regulation. Collectively, our findings provided new insights into the dual functions of ZAT10 on Cd uptake and detoxification in plants and pointed to ZAT10 as a potential gene resource for Cd tolerance improvement in plants.</p

Table_1_ZAT10 plays dual roles in cadmium uptake and detoxification in Arabidopsis.PDF

Cadmium (Cd) is a harmful heavy metal that is risky for plant growth and human health. The zinc-finger transcription factor ZAT10 is highly conserved with ZAT6 and ZAT12, which are involved in Cd tolerance in plants. However, the definite function of ZAT10 in Cd tolerance remains uncertain. Here, we demonstrated that ZAT10 negatively regulated Cd uptake and enhanced Cd detoxification in Arabidopsis. The expression of ZAT10 in plants is induced by Cd treatment. The zat10 mutant plants exhibited a greater sensitivity to Cd stress and accumulated more Cd in both shoot and root. Further investigations revealed that ZAT10 repressed the transcriptional activity of IRT1, which encodes a key metal transporter involved in Cd uptake. Meanwhile, ZAT10 positively regulated four heavy metal detoxification-related genes: NAS1, NAS2, IRT2, and MTP3. We further found that ZAT10 interacts with FIT, but their regulatory relationship is still unclear. In addition, ZAT10 directly bound to its own promoter and repressed its transcription as a negative feedback regulation. Collectively, our findings provided new insights into the dual functions of ZAT10 on Cd uptake and detoxification in plants and pointed to ZAT10 as a potential gene resource for Cd tolerance improvement in plants.</p

Image_1_Antitumor Activity and Treatment-Related Toxicity Associated With Nivolumab Plus Ipilimumab in Advanced Malignancies: A Systematic Review and Meta-Analysis.tif

Combining immune checkpoint inhibitors has shown its efficacy compared to monotherapy in advanced malignancies. We conducted this meta-analysis to provide latest evidence on the objective response rate (ORR) and incidence of treatment-related high-grade adverse events (AEs) during nivolumab and ipilimumab combination treatment and further explore from different drug dose level. PubMed and the 2019 American Society of Clinical Oncology (ASCO) annual meeting abstracts were searched for qualified clinical trials up to June 2019. Of the 23 clinical trials (13 from publications and 11 from ASCO abstracts) included, 2,114 and 2,674 patients were eligible for efficacy and safety analysis, respectively. Pooled analysis suggested that the overall ORR was achieved in 34.5% [95% confidence interval (CI), 29.1–40.4%] of patients. There was no significant difference between nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks (N3I1-Q3W) and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (N1I3-Q3W) arms in ORR [30.8% vs 41%; odds ratio (OR), 0.72; 95% CI, 0.39–1.30; P = 0.275]. Grade 3–4 AEs related to combination therapy occurred in 39.9% (95% CI, 33.5–46.7%) of patients; the most commonly reported grade 3–4 treatment-related AEs were diarrhea (5.28%), colitis (3.96%) and increased alanine aminotransferase (3.51%). Incidence of grade 3–4 AEs were significant lower in N3I1-Q3W arm than in N1I3-Q3W arm (31.3% vs 55.9%; OR 0.52; 95% CI, 0.32–0.87; P = 0.012). Treatment-related death was rare and occurred in 2.0% (95% CI, 1.5–2.7%) of patients. Our comprehensive study provides more precise data on the incidence of treatment-related high-grade AEs and ORR among patients receiving nivolumab and ipilimumab combination regimens. Patients on the N3I1-Q3W arm had comparable ORR and significantly occurred less grade 3–4 AEs than patients on the N1I3-Q3W arm. Our finding is of great importance in assisting clinical trial design and clinical medication choice.</p

Additional file 1 of Serum α-hydroxybutyrate dehydrogenase as a biomarker for predicting survival outcomes in patients with UTUC after radical nephroureterectomy

Supplementary Material 1

DataSheet1_LCK and CD3E Orchestrate the Tumor Microenvironment and Promote Immunotherapy Response and Survival of Muscle-Invasive Bladder Cancer Patients.xlsx

Background: Studies have demonstrated the significance of multiple biomarkers for bladder cancer. Here, we attempt to present biomarkers potentially predictive of the prognosis and immunotherapy response of muscle-invasive bladder cancer (MIBC).Method: Immune and stromal scores were calculated for MIBC patients from The Cancer Genome Atlas (TCGA). Core differential expression genes (DEGs) with prognostic value were identified and validated using an independent dataset GSE31684. The clinical implications of prognostic genes and the inter-gene correlation were presented. The distribution of tumor-infiltrating immune cells (TICs), the correlation with tumor mutation burden (TMB), and the expression of eight immune checkpoint–relevant genes and CD39 were accordingly compared. Two bladder cancer cohorts (GSE176307 and IMvigor210) receiving immunotherapy were recruited to validate the prognostic value of LCK and CD3E for immunotherapy.Results: 361 MIBC samples from TCGA revealed a worse overall survival for higher stromal infiltration (p = 0.009) but a better overall survival for higher immune infiltration (p = 0.042). CD3E and LCK were independently validated by TCGA and GSE31684 to be prognostic for MIBC. CD3E was the most correlative gene of LCK, with a coefficient of r = 0.86 (p + T cells and macrophage M1 are more abundant in favor of a higher expression of CD3E and LCK in MIBC and across pan-cancers. Immune checkpoints like CTLA4, CD274 (PD-1), and PDCD1 (PD-L1) were highly expressed in high-CD3E and high-LCK groups for MIBC and also for pan-cancers, except for thymoma. LCK and CD3E had a moderate positive correlation with CD39 expression. Importantly, high-LCK and high-CD3E groups had a higher percentage of responders than the low-expression groups both in GSE176307 (LCK: 22.73vs. 13.64%, CD3E: 22.00 vs. 13.16%) and IMvigor210 cohorts (LCK: 28.19 vs. 17.45%, CD3E: 25.50 vs. 20.13%).Conclusion: CD3E and LCK were potential biomarkers of MIBC. CD3E and LCK were positively correlated with several regular immunotherapy biomarkers, which is supported by real-world outcomes from two immunotherapy cohorts.</p

Image3_LCK and CD3E Orchestrate the Tumor Microenvironment and Promote Immunotherapy Response and Survival of Muscle-Invasive Bladder Cancer Patients.TIF

Background: Studies have demonstrated the significance of multiple biomarkers for bladder cancer. Here, we attempt to present biomarkers potentially predictive of the prognosis and immunotherapy response of muscle-invasive bladder cancer (MIBC).Method: Immune and stromal scores were calculated for MIBC patients from The Cancer Genome Atlas (TCGA). Core differential expression genes (DEGs) with prognostic value were identified and validated using an independent dataset GSE31684. The clinical implications of prognostic genes and the inter-gene correlation were presented. The distribution of tumor-infiltrating immune cells (TICs), the correlation with tumor mutation burden (TMB), and the expression of eight immune checkpoint–relevant genes and CD39 were accordingly compared. Two bladder cancer cohorts (GSE176307 and IMvigor210) receiving immunotherapy were recruited to validate the prognostic value of LCK and CD3E for immunotherapy.Results: 361 MIBC samples from TCGA revealed a worse overall survival for higher stromal infiltration (p = 0.009) but a better overall survival for higher immune infiltration (p = 0.042). CD3E and LCK were independently validated by TCGA and GSE31684 to be prognostic for MIBC. CD3E was the most correlative gene of LCK, with a coefficient of r = 0.86 (p + T cells and macrophage M1 are more abundant in favor of a higher expression of CD3E and LCK in MIBC and across pan-cancers. Immune checkpoints like CTLA4, CD274 (PD-1), and PDCD1 (PD-L1) were highly expressed in high-CD3E and high-LCK groups for MIBC and also for pan-cancers, except for thymoma. LCK and CD3E had a moderate positive correlation with CD39 expression. Importantly, high-LCK and high-CD3E groups had a higher percentage of responders than the low-expression groups both in GSE176307 (LCK: 22.73vs. 13.64%, CD3E: 22.00 vs. 13.16%) and IMvigor210 cohorts (LCK: 28.19 vs. 17.45%, CD3E: 25.50 vs. 20.13%).Conclusion: CD3E and LCK were potential biomarkers of MIBC. CD3E and LCK were positively correlated with several regular immunotherapy biomarkers, which is supported by real-world outcomes from two immunotherapy cohorts.</p

Image_1_Association of Novel Androgen Receptor Axis-Targeted Therapies With Diarrhea in Patients With Prostate Cancer: A Bayesian Network Analysis.TIF

ObjectiveTo perform a systematic review and network meta-analysis to characterize the effect of novel androgen receptor axis-target (ARAT) agents on diarrhea and constipation.MethodsWe searched the Pubmed, Web of Science, and ClinicalTrials.gov up to September 2021 for phase 3 randomized controlled trials (RCTs) of patients receiving novel ARAT agents for prostate cancer (CaP). A Cochrane risk-of-bias tool was used to assess trial quality. The primary outcomes were risk ratio (RR) of any-grade diarrhea and constipation for patients receiving ARAT treatment. RRs of competing treatments were evaluated by pairwise and Bayesian network meta-analysis.ResultsIn this study, 13 trials with 15,117 participants comparing 5 treatments (abiraterone, enzalutamide, apalutamide, darolutamide, and placebo) were identified. Use of novel ARAT agents was associated with a significant increased risk of any-grade diarrhea (RR = 1.30, 95% CI [1.16, 1.44]). As for subgroup analysis, abiraterone, enzalutamide, and apalutamide were all associated with significant increased risk of any-grade diarrhea (abiraterone: RR = 1.40, 95% CI [1.09, 1.81]; enzalutamide: RR = 1.17, 95% CI [1.02, 1.35]; apalutamide: RR = 1.35, 95% CI [1.03, 1.76]). Based on Bayesian modeling, abiraterone and enzalutamide showed the highest and lowest probability to rank first in terms of increasing risk of any-grade diarrhea. There were no significant differences of risk in any-grade constipation, grade 3 or greater diarrhea, and constipation between ARAT and control group.ConclusionThe present study indicates that the use of novel ARAT agents is associated with a significantly higher risk of diarrhea. Across the four agents, abiraterone may relate to the highest risk of diarrhea among patients with metastatic hormone sensitive prostate cancer (mHSPC) and castration-resistant prostate cancer (CRPC).</p

Table_1_Association of Novel Androgen Receptor Axis-Targeted Therapies With Diarrhea in Patients With Prostate Cancer: A Bayesian Network Analysis.docx

ObjectiveTo perform a systematic review and network meta-analysis to characterize the effect of novel androgen receptor axis-target (ARAT) agents on diarrhea and constipation.MethodsWe searched the Pubmed, Web of Science, and ClinicalTrials.gov up to September 2021 for phase 3 randomized controlled trials (RCTs) of patients receiving novel ARAT agents for prostate cancer (CaP). A Cochrane risk-of-bias tool was used to assess trial quality. The primary outcomes were risk ratio (RR) of any-grade diarrhea and constipation for patients receiving ARAT treatment. RRs of competing treatments were evaluated by pairwise and Bayesian network meta-analysis.ResultsIn this study, 13 trials with 15,117 participants comparing 5 treatments (abiraterone, enzalutamide, apalutamide, darolutamide, and placebo) were identified. Use of novel ARAT agents was associated with a significant increased risk of any-grade diarrhea (RR = 1.30, 95% CI [1.16, 1.44]). As for subgroup analysis, abiraterone, enzalutamide, and apalutamide were all associated with significant increased risk of any-grade diarrhea (abiraterone: RR = 1.40, 95% CI [1.09, 1.81]; enzalutamide: RR = 1.17, 95% CI [1.02, 1.35]; apalutamide: RR = 1.35, 95% CI [1.03, 1.76]). Based on Bayesian modeling, abiraterone and enzalutamide showed the highest and lowest probability to rank first in terms of increasing risk of any-grade diarrhea. There were no significant differences of risk in any-grade constipation, grade 3 or greater diarrhea, and constipation between ARAT and control group.ConclusionThe present study indicates that the use of novel ARAT agents is associated with a significantly higher risk of diarrhea. Across the four agents, abiraterone may relate to the highest risk of diarrhea among patients with metastatic hormone sensitive prostate cancer (mHSPC) and castration-resistant prostate cancer (CRPC).</p

Image2_LCK and CD3E Orchestrate the Tumor Microenvironment and Promote Immunotherapy Response and Survival of Muscle-Invasive Bladder Cancer Patients.TIF

Background: Studies have demonstrated the significance of multiple biomarkers for bladder cancer. Here, we attempt to present biomarkers potentially predictive of the prognosis and immunotherapy response of muscle-invasive bladder cancer (MIBC).Method: Immune and stromal scores were calculated for MIBC patients from The Cancer Genome Atlas (TCGA). Core differential expression genes (DEGs) with prognostic value were identified and validated using an independent dataset GSE31684. The clinical implications of prognostic genes and the inter-gene correlation were presented. The distribution of tumor-infiltrating immune cells (TICs), the correlation with tumor mutation burden (TMB), and the expression of eight immune checkpoint–relevant genes and CD39 were accordingly compared. Two bladder cancer cohorts (GSE176307 and IMvigor210) receiving immunotherapy were recruited to validate the prognostic value of LCK and CD3E for immunotherapy.Results: 361 MIBC samples from TCGA revealed a worse overall survival for higher stromal infiltration (p = 0.009) but a better overall survival for higher immune infiltration (p = 0.042). CD3E and LCK were independently validated by TCGA and GSE31684 to be prognostic for MIBC. CD3E was the most correlative gene of LCK, with a coefficient of r = 0.86 (p + T cells and macrophage M1 are more abundant in favor of a higher expression of CD3E and LCK in MIBC and across pan-cancers. Immune checkpoints like CTLA4, CD274 (PD-1), and PDCD1 (PD-L1) were highly expressed in high-CD3E and high-LCK groups for MIBC and also for pan-cancers, except for thymoma. LCK and CD3E had a moderate positive correlation with CD39 expression. Importantly, high-LCK and high-CD3E groups had a higher percentage of responders than the low-expression groups both in GSE176307 (LCK: 22.73vs. 13.64%, CD3E: 22.00 vs. 13.16%) and IMvigor210 cohorts (LCK: 28.19 vs. 17.45%, CD3E: 25.50 vs. 20.13%).Conclusion: CD3E and LCK were potential biomarkers of MIBC. CD3E and LCK were positively correlated with several regular immunotherapy biomarkers, which is supported by real-world outcomes from two immunotherapy cohorts.</p

Image1_LCK and CD3E Orchestrate the Tumor Microenvironment and Promote Immunotherapy Response and Survival of Muscle-Invasive Bladder Cancer Patients.TIF

Background: Studies have demonstrated the significance of multiple biomarkers for bladder cancer. Here, we attempt to present biomarkers potentially predictive of the prognosis and immunotherapy response of muscle-invasive bladder cancer (MIBC).Method: Immune and stromal scores were calculated for MIBC patients from The Cancer Genome Atlas (TCGA). Core differential expression genes (DEGs) with prognostic value were identified and validated using an independent dataset GSE31684. The clinical implications of prognostic genes and the inter-gene correlation were presented. The distribution of tumor-infiltrating immune cells (TICs), the correlation with tumor mutation burden (TMB), and the expression of eight immune checkpoint–relevant genes and CD39 were accordingly compared. Two bladder cancer cohorts (GSE176307 and IMvigor210) receiving immunotherapy were recruited to validate the prognostic value of LCK and CD3E for immunotherapy.Results: 361 MIBC samples from TCGA revealed a worse overall survival for higher stromal infiltration (p = 0.009) but a better overall survival for higher immune infiltration (p = 0.042). CD3E and LCK were independently validated by TCGA and GSE31684 to be prognostic for MIBC. CD3E was the most correlative gene of LCK, with a coefficient of r = 0.86 (p + T cells and macrophage M1 are more abundant in favor of a higher expression of CD3E and LCK in MIBC and across pan-cancers. Immune checkpoints like CTLA4, CD274 (PD-1), and PDCD1 (PD-L1) were highly expressed in high-CD3E and high-LCK groups for MIBC and also for pan-cancers, except for thymoma. LCK and CD3E had a moderate positive correlation with CD39 expression. Importantly, high-LCK and high-CD3E groups had a higher percentage of responders than the low-expression groups both in GSE176307 (LCK: 22.73vs. 13.64%, CD3E: 22.00 vs. 13.16%) and IMvigor210 cohorts (LCK: 28.19 vs. 17.45%, CD3E: 25.50 vs. 20.13%).Conclusion: CD3E and LCK were potential biomarkers of MIBC. CD3E and LCK were positively correlated with several regular immunotherapy biomarkers, which is supported by real-world outcomes from two immunotherapy cohorts.</p