Serum α-hydroxybutyrate dehydrogenase as a biomarker for predicting survival outcomes in patients with UTUC after radical nephroureterectomy.

PURPOSE: We aimed to determine the prognostic value of α-hydroxybutyrate dehydrogenase (α-HBDH) in upper tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy (RNU). MATERIALS AND METHODS: We retrospectively enrolled the data of 544 UTUC patients at West China Hospital from May 2003 to June 2019. Cancer-specific survival (CSS) was the endpoint of interest. The optimal cutoff value of α-HBDH was identified by X-Tile program. After propensity score matching (PSM), we utilized Kaplan‒Meier curves to estimate survival and Cox proportional hazard model for risk assessment. A nomogram was built based on the results of multivariate analysis, and calibration curve, time-dependent receiver operating characteristic (ROC) curves and decision curve analysis were also performed to evaluate the predictive accuracy. RESULTS: Overall, 394 and 150 patients were divided into the α-HBDH-low group and α-HBDH -high group at the cutoff value of 158 U/L, respectively. After PSM, the two groups were well matched for all confounding factors. High α-HBDH was associated with inferior CSS (P = 0.006), and preoperative α-HBDH was an independent predictor for CSS (HR: 1.36; 95% CI:1.08, 1.80), especially in localized UTUC patients (HR: 2.04; 95% CI:1.11, 3.74). Furthermore, the nomogram based on α-HBDH achieved great predictive ability for CSS with areas under the curves of 0.800 and 0.778 for 3-year and 5-year CSS, respectively. CONCLUSION: Serum α-HBDH was a novel and reliable biomarker for predicting survival outcomes in UTUC patients after RNU but should be further explored.

Preoperative Systemic Inflammation Score Predicts the Prognosis of Patients with Upper Tract Urothelial Carcinoma Undergoing Radical Nephroureterectomy.

Background: To investigate the prognostic significance of systemic inflammation score (SIS) in upper tract urothelial carcinoma (UTUC) in patients undergoing radical nephroureterectomy (RNU). Methods: A total of 313 UTUC patients who underwent RNU at West China Hospital from May 2014 to June 2019 were retrospectively analyzed. The predictive value of SIS for relevant endpoints, including overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS), was assessed by Kaplan-Meier curves and the Cox proportional hazards model. Results: According to inclusion and exclusion criteria, 218 UTUC patients were ultimately included in this cohort study. Statistical analysis shows that increased SIS was significantly associated with higher TNM stage (p = 0.017), lower BMI (p = 0.037), absence of hemoglobin (p < 0.001), and pathologic necrosis (p = 0.007). Kaplan-Meier survival curves clearly visually stratified survival for the three outcomes. After adjusting for tumor grade, the multivariate Cox proportional hazards model results showed that SIS was an independent risk factor for poor OS and CSS (HR = 1.89, 95% CI: 1.11-3.21, p = 0.0183, HR = 1.89, 95% CI: 1.07-3.33, p = 0.0285) in the advanced group. Conclusions: SIS was an independent risk factor for OS and CSS after RNU in patients with high-grade UTUC. It may be a novel and conducive tool for preoperative risk stratification and guiding individualized therapy for high-risk UTUC patients.

Evaluation of Survival Outcomes Among Black and White Patients with Metastatic Castration-resistant Prostate Cancer: A Systematic Review and Meta-analysis.

Context: Data on racial disparities among patients with metastatic castration-resistant prostate cancer (mCRPC) are limited and there is no uniform conclusion on differences by race in this setting. Objective: To provide the latest evidence on racial disparities in survival outcomes between Black and White patients receiving systemic therapies for mCRPC. Evidence acquisition: Our study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We systematically searched the PubMed, Web of Science, and Cochrane Library databases up to September 2023 to identify potentially relevant studies. Overall survival (OS) and progression-free survival (PFS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were evaluated. Evidence synthesis: Nine studies involving 9462 patients with mCRPC (2058 Black and 7404 White men) met the eligibility criteria and were included. Pooled estimates demonstrated significantly better OS for Black than for White men (HR 0.75, 95% CI 0.70-0.80; p < 0.0001). The results were similar in a subgroup of men receiving androgen receptor-targeted therapies (HR 0.72, 95% CI 0.66-0.78; p < 0.0001) and a subgroup of men receiving other treatments (HR 0.79, 95% CI 0.71-0.88; p < 0.0001). Likewise, significantly favorable PFS was observed for Black men receiving ARTs in comparison to their White counterparts (HR 0.84, 95% CI 0.71-0.99; p = 0.0373). Conclusions: Overall, our meta-analysis of survival outcomes for men with mCRPC stratified by race revealed a significant survival benefit for Black men in comparison to their White counterparts, regardless of systemic therapeutic agent. Patient summary: Both biological and nonbiological factors could account for racial differences in the efficacy of systemic treatments for metastatic prostate cancer that is resistant to hormone therapy. Our review provides the latest reliable evidence showing better survival outcomes for Black than for White men. The results will be helpful in further understanding the molecular mechanisms that might explain racial differences in this disease stage and in planning treatment.

Second-line treatment options in metastatic castration-resistant prostate cancer after progression on first-line androgen-receptor targeting therapies: A systematic review and Bayesian network analysis.

OBJECTIVE: To summarize and indirectly compare the efficacy and safety of different second-line systematic therapies after first-line androgen-receptor targeting therapies (ARTs) for biomarker-unselected metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: Studies published in English up to May 2023 were identified in PubMed, Web of Science and ASCO-GU 2023. Studies accessing the efficacy and safety of second-line systematic therapies after first-line ARTs for biomarker-unselected mCRPC patients were eligible for current systematic review and network meta-analysis (NMA). RESULTS: Thirty-two studies with 5388 patients and 10 unique treatment modalities met our inclusion criteria. Current evidence suggested that docetaxel (DOC) combined with the same ART as first-line (ART1) (ART1 + DOC) were associated with significantly improved PSA response, PSA progression-free survival (PFS) and clinical or radiographic PFS (rPFS) compared with other reported second-line systematic therapies, including DOC. An increase in toxicity was observed with ART1 + DOC. Our NMA indicated that DOC monotherapy was only inferior to ART1 + DOC in improvement disease outcomes. The incidence of toxicity between patients received second-line DOC and an alternative ART (ART2) was similar. CONCLUSION: The available evidence reviewed in our work suggested a clinical benefit of DOC nomotherapy and DOC plus ART1 as the second-line systematic therapy for biomarker-unselected mCRPC patients progressed on a first-line ART. More studies and RCTs are needed to evaluate the optimal second-line treatments for mCRPC patients with one prior first-line ART.

Nonsurgical salvage options for locally recurrent prostate cancer after primary definitive radiotherapy: a systematic review and meta-analysis.

OBJECTIVE: To conduct a meta-analysis to provide the latest evidence of nonsurgical local salvage options in the first-line radiotherapy (RT) failure setting for localized prostate cancer patients. BACKGROUND: Recurrence of localized prostate cancer after primary RT remains a clinical challenge. There is no consensus on optimal nonsurgical local salvage therapies, which mainly consist of cryotherapy (CRYO), high-intensity focused ultrasound (HIFU), high/low-dose-rate brachytherapy (HDR/LDR), and stereotactic body radiotherapy (SBRT). METHODS: Our study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The authors systematically searched PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov up to September 2023 to identify potentially relevant studies. The risk of bias was assessed using the European Association of Urology (EAU) items. Biochemical recurrence-free survival (bRFS) and genitourinary/gastrointestinal toxicities were the outcomes of interest. Pooled rates with 95% CIs were evaluated. RESULTS: A total of 99 studies comprising 8440 patients were included. The pooled rate of 1-year biochemical control (BC) was highest for LDR (0.88, 95% CI: 0.72-0.95) and lowest for SBRT (0.68, 95% CI: 0.49-0.83). The pooled rate of 5-year BC was highest for CRYO (0.52, 95% CI: 0.33-0.69) and lowest for HDR (0.23, 95% CI: 0.08-0.51). HIFU presented the worst outcome of grade ≥3 genitourinary toxicities (GU3), with a rate of 0.22 (95% CI: 0.12-0.3). Conversely, CRYO (0.09, 95% CI: 0.04-0.14), HDR (0.05, 95% CI: 0.02-0.07), LDR (0.10, 95% CI: 0.06-0.14), and SBRT (0.06, 95% CI: 0.03-0.09) presented low rates of GU3. All subgroups induced a quite low incidence of grade ≥3 gastrointestinal toxicities (GI3). CONCLUSIONS: Nonsurgical salvage therapies are promising modalities for prostate cancer in the local radiorecurrence setting. Based on the preliminary evidence from this study, CRYO and SBRT might present a relatively steady efficacy of BC with acceptable treatment-related toxicities.

An umbrella review of the evidence associating occupational carcinogens and cancer risk at 19 anatomical sites.

Occupational exposure to carcinogens of increasing cancer risk have been extensively suggested. A robust assessment of these evidence is needed to guide public policy and health care. We aimed to classify the strength of evidence for associations of 13 occupational carcinogens (OCs) and risk of cancers. We searched PubMed and Web of Science up to November 2022 to identify potentially relevant studies. We graded the evidence into convincing, highly suggestive, suggestive, weak, or not significant according to a standardized classification based on: random-effects p value, number of cancer cases, 95% confidence interval of largest study, heterogeneity between studies, 95% prediction interval, small study effect, excess significance bias and sensitivity analyses with credibility ceilings. The quality of meta-analysis was evaluated by AMSTAR 2. Forty-eight articles yielded 79 meta-analyses were included in current umbrella review. Evidence of associations were convincing (class I) or highly suggeastive (class II) for asbestos exposure and increasing risk of lung cancer among smokers (RR = 8.79, 95%CI: 5.81-13.25 for cohort studies and OR = 8.68, 95%CI: 5.68-13.24 for case-control studies), asbestos exposure and increasing risk of mesothelioma (RR = 4.61, 95%CI: 2.57-8.26), and formaldehyde exposure and increasing risk of sinonasal cancer (RR = 1.68, 95%CI: 1.38-2.05). Fifteen associations were supported by suggestive evidence (class III). In summary, the current umbrella review found strong associations between: asbestos exposure and increasing risk of lung cancer among smokers; asbestos exposure and increasing risk of mesothelioma; and formaldehyde exposure and higher risk of sinonasal cancer. Other associations might be genuine, but substantial uncertainty remains.

The Prognostic Value of Preoperative Naples Prognostic Score in Upper Tract Urothelial Carcinoma Patients after Radical Nephroureterectomy.

This study aims to determine the prognostic value of preoperative Naples prognostic score (NPS) on survival outcomes in upper tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy (RNU). We conducted a retrospective study about UTUC patients at West China Hospital from January 2015 to June 2019. The X-Tile program was used to identify the optimal cutoff value of NPS. Overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) were the endpoints of interest. Kaplan-Meier curves were used to estimate survival and Cox proportional hazard model was used for risk assessment. A total of 237 UTUC patients after RNU were identified and the threshold of NPS was determined to be 2. Preoperative high-NPS was associated with inferior OS (p = 0.004), CSS (p = 0.002) and PFS (p = 0.008), especially in locally advanced UTUC patients. Preoperative NPS was an independent predictor for OS (HR: 1.78; 95% CI: 1.08, 2.93), CSS (HR: 1.87; 95% CI: 1.11, 3.14) and PFS (HR: 1.60; 95% CI: 1.02, 2.50). The addition of NPS into the predictive model consisting of predictors from multivariate Cox regression resulted in better prediction performance. Preoperative NPS was a novel and reliable predictor for survival in UTUC patients after RNU, and should be further explored.

A systematic review and meta-analysis for human epidermal growth factor receptor 2 on upper tract urothelial carcinoma patients.

OBJECTIVE: The expression and significance of human epidermal growth factor receptor 2 (Her2) in upper tract urothelial carcinoma (UTUC) remains controversial. Thus, we aimed to systemically review the Her2 expression in UTUC patients and its relationship with pathological characters and clinical outcomes with meta-analysis. MATERIALS AND METHODS: A systematically computerized search in PubMed, Scopus, Embase and Cochrane was conducted. From a total of 454 related articles, 35 articles were finally reviewed and 16 papers were chosen for further analysis. Pathological characters included tumor stage, grade, lymph node metastasis (LNM) and lymphovascular invasion (LVI). The clinical outcomes included overall survival (OS), recurrence-free survival (RFS), cancer specific survival (CSS), metastatic-free survival (MFS) and progression-free survival (PFS). RevMan software was used for meta-analyses. RESULTS: In total 16 studies from 1994 to 2020 were chosen, 14 studies used immunohistochemistry to assess the expression of Her2 and 5 studies used in situ hybridization, with a positive rate of 0 to 74.0% and 7.2 to 18.1%, respectively. Her2-positive was significantly associated with stage (pooled HR 1.86; 95 % CI 1.43-2.42), grade (pooled HR 2.81; 95 % CI 1.01-7.85) and LNM (pooled HR 1.93; 95 % CI 1.18-3.15). However, there was no statistically relationship between Her2-positive with LVI (pooled HR 1.48; 95 % CI 0.64-3.46) and RFS (pooled HR 1.41; 95 % CI 0.98-1.83). CONCLUSIONS: This review indicated that UTUC patients with Her2-positive tended to develop higher stage and grade tumors and LNM. The Her2 expression in UTUC patients deserves further investigation in the future.

Survival impact of variant histology in patients with upper tract urothelial carcinoma after radical nephroureterectomy.

OBJECTIVE: To investigate the prognostic impact of variant histology (VH) on survival outcomes in upper tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy (RNU). MATERIALS AND METHODS: Data from 635 UTUC patients who underwent RNU at our institution from May 2003 to June 2019 were retrospectively acquired and analyzed. After propensity score matching (PSM), we investigated the impact of VH on overall survival (OS) and cancer-specific survival (CSS) by using cumulative incidence plots with the log-rank test, Cox regression models, and competing risk regression models. RESULTS: Overall, 121 (19.1%) patients were diagnosed with VH, including 68 (10.7%) with squamous cell differentiation (SCD) and 28 (4.4%) with adenocarcinoma differentiation (AD). After PSM, the presence of VH was significantly associated with worse OS (HR 1.70, 95% CI 1.25-2.32) and CSS (HR 1.64, 95% CI 1.17-2.31) only in locally advanced UTUC patients (pT>2). In the subgroup analysis, SCD revealed inferior outcomes (OS: HR 1.81, 95% CI 1.28-2.57; CSS: HR 1.73, 95% CI 1.18-2.54) compared with pure urothelial carcinoma (pUC), whereas AD conferred comparable outcomes. In addition, compared with pUC patients, SCD patients with extensive squamous components had significantly decreased OS (HR 4.17, 95% CI 1.84-9.44) and CSS (HR 1.10, 95% CI 0.61-1.99), whereas those with regional squamous components had similar survival outcomes. CONCLUSION: For UTUC patients after RNU, the presence of VH is associated with aggressive clinicopathological features and inferior survival outcomes. However, the survival outcomes of localized UTUC patients (pT≤2) with VH, and patients with the AD or regional SCD subtype are comparable to those of patients with pUC.

Advanced Age May Not Be an Absolute Contraindication for Radical Nephroureterectomy in Patients with Upper Tract Urothelial Carcinoma: A Single-Center Case Series and a Systematic Review with Meta-Analyses.

OBJECTIVE: This study aims to investigate whether advanced age is an absolute contraindication for radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC) through a single-center case series and a systematic review with meta-analysis. MATERIALS AND METHODS: In the single-center case series, 588 UTUC patients who underwent RNU between May 2003 and June 2019 in West China Hospital were enrolled, and cancer-specific survival (CSS) was the primary outcome of interest. In the systematic review with meta-analysis, PubMed, Scopus, Embase, and Cochrane databases were systematically searched for related articles for further analysis. The endpoints for meta-analyses were overall survival (OS) and CSS. RESULTS: The single-center case series included 57 (9.7%) octogenarians. The CSS of octogenarians after RNU was comparable to that of younger people. Advanced age (≥80) was not an independent risk factor for poor CSS (HR, 1.08; 95% CI, 0.48, 2.40). In a systematic review with meta-analysis, the cut-off value of advanced age is 70, and the results showed that advanced age was associated with inferior OS (pooled HR, 1.55; 95% CI, 1.29, 2.01) and CSS (pooled HR, 1.37; 95% CI, 1.08, 1.65). However, the subgroup analysis of countries found no positive correlation between advanced age and CSS (pooled HR, 1.33; 95% CI 0.92, 1.74) in Chinese. CONCLUSIONS: Advanced age may no longer be an absolute contraindication for RNU. RNU can be safely and effectively performed on UTUC patients of advanced age after a comprehensive presurgical evaluation.

Combining Novel Hormonal Therapies with a Poly (ADP-Ribose) Polymerase Inhibitor for Metastatic Castration-Resistant Prostate Cancer: Emerging Evidence.

Preclinical and clinical studies have suggested potential synergies of combining poly (ADP-ribose) polymerase (PARP) inhibitors and novel hormonal therapies (NHT) for patients with metastatic castration-resistant prostate cancer (mCRPC). We systematically searched PubMed, ClinicalTrials.gov and ASCO-GU annual meeting abstracts up to March 2023 to identify potential phase III trials reporting the use of combining PARP inhibitors with NHT in the first-line setting for mCRPC. A total of four phase III trials met the criteria for subsequent review. Emerging data suggested that the radiographic progression-free survival (rPFS) was significantly longer in the PARP inhibitor combined with NHT group versus the placebo plus NHT group for the first-line setting of biomarker-unselected mCRPC patients, especially for patients with homologous recombination repair (HRR) mutation (HRR m), and with the greatest benefit for BRCA1/2 mutation (BRCA1/2 m) populations. Final overall survival (OS) data of the PROpel trial indicated a significant improvement in median OS for mCRPC patients with HRR m and BRCA1/2 m receiving olaparib + abiraterone. Prior taxane-based chemotherapy might not influence the efficacy of the combination. Compared with the current standard-of-care therapies, combining NHT with PARP inhibitors could achieve a significant survival benefit in the first-line setting for mCRPC patients with HRR and BRCA1/2 mutations.

The Role of cGAS-STING in Age-Related Diseases from Mechanisms to Therapies.

With aging, the incidence of age-related diseases increases. Hence, age-related diseases are inevitable. However, the mechanisms by which aging leads to the onset and progression of age-related diseases remain unclear. It has been reported that inflammation is closely associated with age-related diseases and that the cGAS-STING signaling pathway, which can sense the aberrant presence of cytosolic DNA during aging and induce an inflammatory response, is an important mediator of inflammation in age-related diseases. With a better understanding of the structure and molecular biology of the cGAS-STING signaling axis, numerous selective inhibitors and agonists targeting the cGAS-STING pathway in human age-related diseases have been developed to modulate inflammatory responses. Here, we provide a narrative review of the activity of the cGAS-STING pathway in age-related diseases and discuss its general mechanisms in the onset and progression of age-related diseases. In addition, we outline treatments targeting the cGAS-STING pathway, which may constitute a potential therapeutic alternative for age-related diseases.

ZmSIZ1a and ZmSIZ1b play an indispensable role in resistance against Fusarium ear rot in maize.

Fusarium ear rot (FER) is a destructive fungal disease of maize caused by Fusarium verticillioides. FER resistance is a typical complex quantitative trait controlled by micro-effect genes, leading to difficulty in identifying the host resistance genes. SIZ1 encodes a SUMO E3 ligase regulating a wide range of plant developmental processes and stress responses. However, the function of ZmSIZ1 remains poorly understood. In this study, we demonstrate that ZmSIZ1a and ZmSIZ1b possess SUMO E3 ligase activity, and that the Zmsiz1a/1b double mutant, but not the Zmsiz1a or Zmsiz1b single mutants, exhibits severely impaired resistance to FER. Transcriptome analysis showed that differentially expressed genes were significantly enriched in plant disease resistance-related pathways, especially in plant-pathogen interaction, MAPK signalling, and plant hormone signal transduction. Thirty-five candidate genes were identified in these pathways. Furthermore, the integration of the transcriptome and metabolome data revealed that the flavonoid biosynthesis pathway was induced by F. verticillioides infection, and that accumulation of flavone and flavonol was significantly reduced in the Zmsiz1a/1b double mutant. Collectively, our findings demonstrate that ZmSIZ1a and ZmSIZ1b play a redundant, but indispensable role against FER, and provide potential new gene resources for molecular breeding of FER-resistant maize cultivars.

Pyroptosis in urinary malignancies: a literature review.

Urinary neoplasms refer to malignant tumours occurring in any part of the urinary system, including the kidney, renal pelvis, ureter, bladder, prostate, etc. The worldwide incidence of urinary system tumours has been increasing yearly. Available methods include surgical treatment, radiotherapy, chemotherapy, endocrine therapy, molecular targeted therapy, and immune therapy. In recent years, emerging evidence has demonstrated that cell pyroptosis plays an important role in the occurrence and progression of malignant urinary tumours. Pyroptosis is a new type of cell death that involves inflammatory processes regulated by gasdermins (GSDMs) and is characterized by membrane perforation, cell swelling and cell rupture. Recent studies have shown that pyroptosis can inhibit and promote the development of tumours. This manuscript reviews the role of pyroptosis in the development and progression of prostate cancer, kidney cancer and bladder cancer and introduces the latest research results in these fields to discuss the therapeutic potential of the pyroptosis pathway in urinary malignancies.

Which Type of Exercise During Radiation Therapy Is Optimal to Improve Fatigue and Quality of Life in Men with Prostate Cancer? A Bayesian Network Analysis.

Context: Physical exercise in men with prostate cancer (CaP) has shown benefits in improving cancer-related fatigue (CRF) and quality of life (QoL) during radiation therapy. However, types of exercises that are more effective are not well understood. Evidence acquisition: We searched PubMed, Web of Science, and ClinicalTrials.gov up to November 2021 to identify potentially relevant studies. Randomized controlled trials (RCTs) testing the effects of exercise training on CRF, QoL, and treatment-related toxicities in patients with CaP undergoing radiation therapy were included. The quality of individual studies was evaluated using the Tool for the assEssment of Study qualiTy and reporting in Exercise (TESTEX) scale. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation method. A meta-regression analysis was conducted to test the study-level covariates. A random-effect network meta-analysis was conducted based on a Bayesian model. Evidence synthesis: Eight RCTs with 466 participants were included. Exercise achieved significant improvements in CRF (standardized mean difference [SMD] = 1.24, 95% confidence interval or CI [0.43, 2.06], I2 = 93%) and QoL (SMD = 1.40, 95% CI [0.05, 2.75], I2 = 95%). Based on the meta-regression and Bayesian model, combined moderate-intensity continuous training aerobic exercise and resistance exercise (MICT/RES) showed the highest probability of ranking first in terms of CRF and QoL improvement, but the results of QoL were unstable. Exercise training also had a positive effect on urinary toxicities (SMD = -0.53, 95% CI [-0.79, -0.27], I2 = 0%). A subgroup analysis indicated that MICT/RES might be the most promising exercise modality for reducing intestinal toxicities (SMD = -1.76, 95% CI [-2.32, -1.20]). Conclusions: MICT/RES might be superior to any other types of exercise at reducing CRF. MICT/RES was more effective on significantly mitigating urinary and intestinal toxicities. Patient summary: In prostate cancer (CaP) survivors during radiation therapy, exercise training is an effective and safe intervention to reduce cancer-related fatigue (CRF) and improve quality of life (QoL), and should be prescribed as a rehabilitation option for clinical management. As for the types of exercises, moderate-intensity continuous training aerobic exercise and resistance exercise seem to be the most effective interventions to reduce CRF, improve QoL, and mitigate treatment-related symptoms.

ZAT10 plays dual roles in cadmium uptake and detoxification in Arabidopsis.

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.

Cysteines have a role in conformation of the UVR8 photoreceptor.

The UV RESISTANCE LOCUS 8 (UVR8) photoreceptor mediates plant responses to Ultraviolet-B (UV-B) wavelengths. The UVR8 dimer dissociates into monomers following UV-B photoreception, a process accompanied by conformational changes that facilitate interaction of UVR8 with proteins that initiate responses. However, the importance of particular amino acids in maintaining UVR8 conformation and modulating protein interactions is poorly understood. Here we examine the roles of cysteine amino acids C231 and C335 in UVR8 structure and function. UVR8C231S,C335S mutant protein forms dimers and monomerizes similarly to wild-type UVR8. UVR8C231S,C335S interacts with CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) in plants to initiate photomorphogenic responses to UV-B, although the interaction is weaker when examined in yeast two-hybrid assays. Similarly, the interaction of UVR8C231S,C335S with REPRESSOR OF UV-B PHOTOMORPHOGENESIS (RUP) proteins is weaker in both plants and yeast compared with wild-type UVR8. Re-dimerization of UVR8 in plants, which is mediated by RUP proteins, occurs with reduced efficiency in UVR8C231S,C335S . Fluorescence resonance energy transfer analysis indicates that UVR8C231S,C335S has an altered conformation in plants, in that the N- and C-termini appear closer together, which may explain the altered protein interactions.

CXCL8 in Tumor Biology and Its Implications for Clinical Translation.

The chemokine CXCL8 has been found to play an important role in tumor progression in recent years. CXCL8 activates multiple intracellular signaling pathways by binding to its receptors (CXCR1/2), and plays dual pro-tumorigenic roles in the tumor microenvironment (TME) including directly promoting tumor survival and affecting components of TME to indirectly facilitate tumor progression, which include facilitating tumor cell proliferation and epithelial-to-mesenchymal transition (EMT), pro-angiogenesis, and inhibit anti-tumor immunity. More recently, clinical trials indicate that CXCL8 can act as an independently predictive biomarker in patients receiving immune checkpoint inhibitions (ICIs) therapy. Preclinical studies also suggest that combined CXCL8 blockade and ICIs therapy can enhance the anti-tumor efficacy, and several clinical trials are being conducted to evaluate this therapy modality.

The associations between organophosphate esters and urinary incontinence in the general US population.

Organophosphate esters (OPEs) impact health in many ways. Since its relationship with urinary incontinence remains unknown, we aimed to explore their associations in the US general population. We combined the results of urine specimens test and self-reported urinary incontinence conditions from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 among 2666 participants and then conducted linear regression and logistic regression to analyse associations between log2-transformed OPE concentrations and urinary incontinence. We found that 0.92% of men and 15.74% of women complained of mixed urinary incontinence (MUI). The concentrations of diphenyl phosphate (DPHP) were significantly correlated to MUI among women when treated as a continuous variable (adjusted odds ratio (OR) = 1.15; 95% confidence interval (CI), 1.01-1.31; p = 0.0369) and as a categorical variable (adjusted OR = 1.24; 95% CI, 1.03-1.49; p for trend = 0.0245), whereas no positive correlation was found in males. There were no significant associations between the other three OPEs: bis(2-chloroethyl) phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and dibutyl phosphate (DBUP). The association of DPHP with an increased prevalence OR of MUI in women is a public health concern; future prospective studies are needed to explore its potential mechanism.

Association of the inflammatory potential of diet and lower urinary tract symptoms among men in the United States.

BACKGROUND: Inflammation is crucial in the pathogenesis of lower urinary tract symptoms (LUTS) in men. Diet modulates inflammation. Therefore, diet could be a modifiable factor in male LUTS prevention and treatment. We aimed to investigate the association between dietary inflammatory potential and male LUTS. METHODS: We used two cycles of National Health and Nutrition Examination Survey (NHANES) with self-report LUTS data. We calculated the dietary inflammatory index (DII) based on a 24 h diet recall and evaluated male LUTS. Clinical LUTS was defined as two or more coexisting symptoms. We used univariate and multivariate logistic regression models, the smooth curve fitting to analyze the relationship between clinical LUTS and the DII score. Subgroup analyses were conducted. RESULTS: We observed a positive non-linear relationship between clinical LUTS and DII. We found that when DII was higher than the inflection point 2.39, a 1-unit increase in DII was associated with 26.1% higher adjusted odds of clinical LUTS. Subgroup analyses showed that the DII score was only positively correlated with clinical LUTS risk in non-drinkers, smokers, and non-obese people (DII >2.39). CONCLUSIONS: Inflammation might be the key mechanism bridging dietary consumption to male LUTS. Excessive pro-inflammatory food intake (DII >2.39) warrants special vigilance, especially for non-drinkers, smokers, and non-obese men.