Pan-cancer analysis of polo-like kinase family genes reveals polo-like kinase 1 as a novel oncogene in kidney renal papillary cell carcinoma.

Background: Polo-like kinases (PLKs) are a kinase class of serine/threonine with five members that play crucial roles in cell cycle regulation. However, their biological functions, regulation, and expression remain unclear. This study revealed the molecular properties, oncogenic role, and clinical significance of PLK genes in pan-cancers, particularly in kidney renal papillary cell carcinoma (KIRP). Methods: We evaluated the mutation landscape, expression level, and prognostic values of PLK genes using bioinformatics analyses and explored the association between the expression level of PLK genes and tumor microenvironment (TME), immune subtype, cancer immunotherapy, tumor stemness, and drug sensitivity. Finally, we verified the prognostic value in patients with KIRP through univariate and multivariate analyses and nomogram construction. Results: PLK genes are extensively altered in pan-cancer, which may contribute to tumorigenesis. These genes are aberrantly expressed in some types of cancer, with PLK1 being overexpressed in 31 cancers. PLK expression is closely associated with the prognosis of various cancers. The expression level of PLK genes is related with sensitivity to diverse drugs and cancer immunity as well as cancer immunotherapy. Importantly, we verified that PLK1 was overexpressed in KIRP tissues and could be an unfavorable prognostic biomarker in patients with KIRP. Hence, PLK1 may serve as an oncogenic gene in KIRP and should be explored in future studies. Conclusions: Our study comprehensively reports the molecular characteristics and biological functions of PLK family gens across human cancers and recommends further investigation of these genes as potential biomarkers and therapeutic targets, especially in KIRP.

Deleting SUV39H1 in CAR-T cells epigenetically enhances the antitumor function.

SUV39H1 ablation in CAR-T cells epigenetically enhances the antitumor function (by Figdraw). (A) Schematic illustration of SUV39H1 ablation-mediated enhanced antitumor function of CAR-T cells. Functional CAR-T cells eventually transformed into dysfunctional exhausted CAR-T cells under the exposure of chronic tumor antigens, accompanied by reduced proliferation level, effector function, and stemness/memory characteristics, thereby limiting the antitumor activity so as to cause the recurrence of solid tumors. Upon genetic engineering of SUV39H1 ablation, SUV KO CAR-T cells are endowed with increased proliferation level and stemness/memory properties, accompanied by reduced effector/exhausted phenotype. Augmented SUV KO CAR-T cells after in vitro expansion intravenously infusion to mice achieved stronger and more persistent tumor rejection. (B) SUV39H1 ablation-mediated epigenetic reprogramming mechanism of CAR-T cells. Epigenetically, under the stimulation of chronic tumor antigens, exhausted CAR-T cells were characterized by downregulation of proliferation, effector and stemness/memory-associated genes and upregulation of exhaustion-associated genes. SUV39H1 genetic ablation increased chromatin accessibility of stemness/memory-associated genes and reduced chromatin accessibility of inhibitory receptors and effector-associated genes in SUV KO CAR-T cells, epigenetically reprogramming human T cells to express higher levels of stemness/memory genes such as KLF2, LEF1 and TCF7 and lower levels of effector/exhaustion genes.

Unlocking the power of nanomedicine: Cell membrane-derived biomimetic cancer nanovaccines for cancer treatment.

Over the past decades, nanomedicine researchers have dedicated their efforts to developing nanoscale platforms capable of more precisely delivering drug payloads to attack tumors. Cancer nanovaccines are exhibiting a distinctive capability in inducing tumor-specific antitumor responses. Nevertheless, there remain numerous challenges that must be addressed for cancer nanovaccines to evoke sufficient therapeutic effects. Cell membrane-derived nanovaccines are an emerging class of cancer vaccines that comprise a synthetic nanoscale core camouflaged by naturally derived cell membranes. The specific cell membrane has a biomimetic nanoformulation with several distinctive abilities, such as immune evasion, enhanced biocompatibility, and tumor targeting, typically associated with a source cell. Here, we discuss the advancements of cell membrane-derived nanovaccines and how these vaccines are used for cancer therapeutics. Translational endeavors are currently in progress, and additional research is also necessary to effectively address crucial areas of demand, thereby facilitating the future successful translation of these emerging vaccine platforms.

ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion.

Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models across various solid tumor types. The antibody targeting canine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurring tumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3ε ligand 1) in impeding T cell activation during the critical "signal one" phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.

The application of HER2-ADC in future: More than expression.

We analyzed the potential of HER2-targeted antibody-drug conjugates (ADCs) in treating NSCLC with activating HER2 mutations. We identified specific mutations, notably G776delinsVC, that are associated with higher therapeutic response rates, suggesting a refined approach for precision treatment. Further validation and exploration are crucial for potential breakthroughs in ADC therapy.

Do the same chlorinated organophosphorus flame retardants that cause cytotoxicity and DNA damage share the same pathway?

Organophosphorus flame retardants (OPFRs) have been frequently detected with relatively high concentrations in various environmental media and are considered emerging environmental pollutants. However, their biological effect and underlying mechanism is still unclear, and whether chlorinated OPFRs (Cl-OPFRs) cause adverse outcomes with the same molecular initial events or share the same key events (KEs) remains unknown. In this study, in vitro bioassays were conducted to analyze the cytotoxicity, mitochondrial impairment, DNA damage and molecular mechanisms of two Cl-OPFRs. The results showed that these two Cl-OPFRs, which have similar structures, induced severe cellular and molecular damages via different underlying mechanisms. Both tris(2-chloroethyl) phosphate (TCEP) and tris(1-chloro-2-propyl) (TCPP) induced oxidative stress-mediated mitochondrial impairment and DNA damage, as shown by the overproduction of intracellular reactive oxygen species (ROS) and mitochondrial superoxide. Furthermore, the DNA damage caused by TCPP resulted in p53/p21-mediated cell cycle arrest, as evidenced by flow cytometry and real-time PCR. At the cellular and molecular levels, TCPP increased the sub-G1 apoptotic peak and upregulated the p53/Bax apoptosis pathway, possibly resulted in apoptosis associated with its stronger cytotoxicity. Although structurally similar to TCPP, TCEP did not induce mitochondrial impairment and DNA damage by the same KEs. These results provide insight into the toxicity of Cl-OPFRs with similar structures but different mechanisms, which is of great significance for constructing adverse outcome pathways or determining intermediate KEs.

Risk and mechanisms of phosphorus release at the sediment-water interface of lakes in cold and arid regions during non-frozen seasons.

In recent years, the eutrophication of lakes has accelerated in cold arid regions; the release of nutrients from sediments is an important contributor. The sequential extraction method, high-resolution peeper (HR-Peeper), and diffusive gradients in thin films (DGT) techniques were used to study the occurrence characteristics, release risk, and release mechanism of phosphorus (P) at the sediment-water interface (SWI) of Ulanor Wetland in the Hulun Lake Basin, Inner Mongolia, China. The mean total P concentration in overlying water was lower in August than that in May. Dissolved organic P (DOP) or particulate P (PP) was the main form of P in the overlying water. PP dominates in May and DOP in August. Refractory P was the main form of P in sediments. The concentrations of soluble reactive P and DGT-active P in the pore water of the sediment column were higher than those in the overlying water, and the concentrations were higher in August than those in May. Release of P in the wetland sediments occurred during the non-frozen seasons, with a higher risk in August than in May. The good linear correlation between dissolved P, Fe, and Mn in the DGT profiles verified their co-release due to the anaerobic reduction of Fe/Mn oxides. Moreover, alkaline sediments are also conducive to the release of sediment P. This study can provide data and theoretical support for eutrophication control in Ulanor Wetland and other similar water bodies in cold and arid regions.

Characterization of phosphate solubilizing bacteria in the sediments of eutrophic lakes and their potential for cyanobacterial recruitment.

Microbes may induce endogenous phosphorus (P) migration from lacustrine sediment. This study focused on the role of phosphate-solubilizing bacteria (PSB) disturbance in affecting the sediment P release and further contributing to cyanobacterial recruitment in Meiliang Bay, Lake Taihu. Gluconic acid was the main mechanism of phosphate solubilizing by PSB. The dominant PSB (Burkholderia) isolated from eutrophic lake sediments was used as a representative to investigate the effects of disturbance on endogenous P release using diffusive gradients in thin films (DGT) and high-resolution dialysis (HR-Peeper). The results show that soluble reactive phosphorus (SRP) and iron (Fe (II)) concentrations could reach 0.51 mg L-1 and 33.56 mg L-1 in pore water, respectively. And the sediment DGT-P and DGT-Fe were relatively reduced by PSB. Subsequent the chlorophyll a (Chl a) concentrations reached peaks of 344.8 µg L-1 in overlying water. The abundance of the dominant PSB (Burkholderia-Caballeronia-Paraburkholderia) were significantly associated with Chl a (P < 0.05) and algal effective state phosphorus (AAP) (P < 0.05), respectively. PSB mainly regulates AAP leaching to pore water and then diffusing across the sediment-water interface to the overlying water, producing the effect of cyanobacteria recruitment. The results provide new insights into early management of cyanobacterial resuscitation in a large eutrophic lake.

Mobilizing China and the Global Community to Confront the Treatment Desert for Pediatric Solid Tumors.

SUMMARY: Pediatric solid tumors are distinct clinical entities that impose heavy socioeconomic burden and while their incidence has increased in recent years, treatment options are often limited, with only 27 drugs approved for pediatric solid tumors in the United States, and fewer still, 13, in China. The scale of the unmet medical need is immense and new efforts are urgently needed to develop efficient therapeutics and improve these children's lives.

Global environmental and toxicological impacts of polybrominated diphenyl ethers versus organophosphate esters: A comparative analysis and regrettable substitution dilemma.

The prevalence of organophosphate esters (OPEs) in the global environment is increasing, which aligns with the decline in the usage of polybrominated diphenyl ethers (PBDEs). PBDEs, a category of flame retardants, were banned and classified as persistent organic pollutants (POPs) through the Stockholm Convention due to their toxic and persistent properties. Despite a lack of comprehensive understanding of their ecological and health consequences, OPEs were adopted as replacements for PBDEs. This research aims to offer a comparative assessment of PBDEs and OPEs in various domains, specifically focusing on their persistence, bioaccumulation, and toxicity (PBT) properties. This study explored physicochemical properties (such as molecular weight, octanol-water partition coefficient, octanol-air partition coefficient, Henry's law constant, and vapor pressures), environmental behaviors, global concentrations in environmental matrices (air, water, and soil), toxicities, bioaccumulation, and trophic transfer mechanisms of both groups of compounds. Based on the comparison and analysis of environmental and toxicological data, we evaluate whether OPEs represent another instance of regrettable substitution and global contamination as much as PBDEs. Our findings indicate that the physical and chemical characteristics, environmental behaviors, and global concentrations of PBDEs and OPEs, are similar and overlap in many instances. Notably, OPE concentrations have even surged by orders of several magnitude compared to PBDEs in certain pristine regions like the Arctic and Antarctic, implying long-range transport. In many instances, air and water concentrations of OPEs have been increased than PBDEs. While the bioaccumulation factors (BAFs) of PBDEs (ranging from 4.8 to 7.5) are slightly elevated compared to OPEs (-0.5 to 5.36) in aquatic environments, both groups of compounds exhibit BAF values beyond the threshold of 5000 L/kg (log10 BAF > 3.7). Similarly, the trophic magnification factors (TMFs) for PBDEs (ranging from 0.39 to 4.44) slightly surpass those for OPEs (ranging from 1.06 to 3.5) in all cases. Metabolic biotransformation rates (LogKM) and hydrophobicity are potentially major factors deciding their trophic magnification potential. However, many compounds of PBDEs and OPEs show TMF values higher than 1, indicating biomagnification potential. Collectively, all data suggest that PBDEs and OPEs have the potential to bioaccumulate and transfer through the food chain. OPEs and PBDEs present a myriad of toxicity endpoints, with notable overlaps encompassing reproductive issues, oxidative stress, developmental defects, liver dysfunction, DNA damage, neurological toxicity, reproductive anomalies, carcinogenic effects, and behavior changes. Based on our investigation and comparative analysis, we conclude that substituting PBDEs with OPEs is regrettable based on PBT properties, underscoring the urgency for policy reforms and effective management strategies. Addressing this predicament before an exacerbation of global contamination is imperative.

Seasonal variations in spatial distribution, mobilization kinetic and toxicity risk of arsenic in sediments of Lake Taihu, China.

This study investigated seasonal variations in spatial distribution, mobilization kinetic and toxicity risk of arsenic (As) in sediments of three representative ecological lakes in Lake Taihu. Results suggested that the bioavailability and mobility of As in sediments depended on the lake ecological types and seasonal changes. At the algal-type zones and macrophyte-type zones, elevated As concentrations were observed in April and July, while these occurred at the transition areas in July and October. The diffusion flux of soluble As ranged from 0.03 to 3.03 ng/cm2/d, indicating sediments acted as a source of As. Reductive dissolution of As-bearing iron/manganese-oxides was the key driver of sediment As remobilization. However, labile S(-II) caused by the degradations of algae and macrophytes buffered sediment As release at the algal-type and macrophyte-type zones. Furthermore, the resupply ratio was less than 1 at three ecological lakes, indicating the resupply As capacity of sediment solid phase was partially sustained case. The risk quotient values were higher than 1 at the algal-type zones and transition areas in July, thereby, the adverse effects of As should not be ignored. This suggested that it is urgently need to be specifically monitored and managed for As contamination in sediments across multi-ecological lakes.

Predictive value of 18 F-FDG PET/CT and serum tumor markers for tumor mutational burden in patients with non-small cell lung cancer.

PURPOSE: To investigate the correlations between metabolic parameters (MPs) of 18 F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT), serum tumor markers (STMs), and tumor mutational burden (TMB) in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: In this retrospective study, we enrolled 129 patients with NSCLC (males, 78; females, 51) who underwent baseline TMB and STM tests and 18 F-FDG PET/CT scans before treatment between March 2018 and September 2022. Patients were categorized into TMB-high (TMB ≥10 mutations/Mb; n = 27 [20.9%]) and non-TMB-high (TMB <10 mutations/Mb; n = 102 [79.1%]) groups. Binary logistic regression analyses were performed to determine independent predictors of TMB-high. Univariate and multivariate linear regression analyses were performed to determine independent predictors of TMB level on a log scale. Subgroup analyses for adenocarcinoma (ADC), ADC with EGFR+, ADC with EGFR-, and squamous cell carcinoma (SCC) were performed. RESULTS: For ADC, all MPs (SULpeak , SULmax , SULmean , MTV, and TLG) were significantly higher in the TMB-high group than the non-TMB-high group; smoker (odds ratio [OR] = 27.08, p = 0.018), EGFR+ (OR = 0.03, p = 0.033), KRAS+ (OR = 7.98, p = 0.083), high CEA (OR = 33.56, p = 0.029), and high CA125 (OR = 13.68, p = 0.030) were independent predictors of TMB-high; and all MPs showed significant positive linear correlations with TMB on a log scale, with SULpeak as an independent predictor. However, no significant correlation was observed for SCC. CONCLUSION: MPs and STMs can predict the TMB level for patients with ADC, and may serve as potential substitutes for TMB with increased value and easy implementation in guiding immunotherapy through noninvasive methods.

KCNAB2 overexpression inhibits human non-small-cell lung cancer cell growth in vitro and in vivo.

Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. NSCLC patients often have poor prognosis demanding urgent identification of novel biomarkers and potential therapeutic targets. KCNAB2 (regulatory beta subunit2 of voltage-gated potassium channel), encoding aldosterone reductase, plays a pivotal role in regulating potassium channel activity. In this research, we tested the expression of KCNAB2 as well as its potential functions in human NSCLC. Bioinformatics analysis shows that expression of KCNAB2 mRNA is significantly downregulated in human NSCLC, correlating with poor overall survival. In addition, decreased KCNAB2 expression was detected in different NSCLC cell lines and local human NSCLC tissues. Exogenous overexpression of KCNAB2 potently suppressed growth, proliferation and motility of established human NSCLC cells and promoted NSCLC cells apoptosis. In contrast, CRISPR/Cas9-induced KCNAB2 knockout further promoted the malignant biological behaviors of NSCLC cells. Protein chip analysis in the KCNAB2-overexpressed NSCLC cells revealed that KCNAB2 plays a possible role in AKT-mTOR cascade activation. Indeed, AKT-mTOR signaling activation was potently inhibited following KCNAB2 overexpression in NSCLC cells. It was however augmented by KCNAB2 knockout. In vivo, the growth of subcutaneous KCNAB2-overexpressed A549 xenografts was significantly inhibited. Collectively, KCNAB2 could be a novel effective gene for prognosis prediction of NSCLC. Targeting KCNAB2 may lead to the development of advanced therapies.

Immune checkpoint inhibitor-associated myocarditis: a systematic analysis of case reports.

Background: Immune checkpoint inhibitors (ICIs) therapy can be complicated by their potential cardiovascular toxicities, including myocarditis. Nowadays, no prospective trials have focused on ICI-associated myocarditis optimized management. Available evidence only come from case reports or series. A systematic case reports analysis was conducted to collect and evaluate emerging evidence of ICI-associated myocarditis to provide more information to clinicians. Methods: We performed a literature search for eligible case reports or series published between January 2018 and May 2023 using the PubMed database. Then, we extracted interesting information via table form. Finally, this study included 113 publications on 106 patients with ICI-associated myocarditis. Results: Myocarditis was found to be a highly life-threatening disease, with 53.8% of cases. Over half of cases were life-threatening (G4, 23.6%) or severe (G3, 35.8%) and required glucocorticoids. Higher rates of improvement were associated with the best response to ICI for complete response/partial response (72.7% vs. 53.9%), glucocorticoid administration (30% vs. 22%), and discontinuation of ICI (58.8% vs. 32.1%). Consequently, ICI-associated G3-G4 myocarditis should be treated with a combination of discontinuation of ICIs, high-dose glucocorticoids, other drugs, chemical drugs, plasma exchange, and life support. For moderate G1 or G2 cases, discontinuation of ICIs and regular-dose glucocorticoids should be considered. Conclusion: Once full recovery or improvement was achieved; glucocorticoids can be administered at low doses or stopped. Notably, re-challenge with ICIs appears feasible after resolution or meaningful improvement of myocarditis.