Associations of genetic risk, BMI trajectories, and the risk of non-small cell lung cancer: a population-based cohort study.

BACKGROUND: Body mass index (BMI) has been found to be associated with a decreased risk of non-small cell lung cancer (NSCLC); however, the effect of BMI trajectories and potential interactions with genetic variants on NSCLC risk remain unknown. METHODS: Cox proportional hazards regression model was applied to assess the association between BMI trajectory and NSCLC risk in a cohort of 138,110 participants from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. One-sample Mendelian randomization (MR) analysis was further used to access the causality between BMI trajectories and NSCLC risk. Additionally, polygenic risk score (PRS) and genome-wide interaction analysis (GWIA) were used to evaluate the multiplicative interaction between BMI trajectories and genetic variants in NSCLC risk. RESULTS: Compared with individuals maintaining a stable normal BMI (n = 47,982, 34.74%), BMI trajectories from normal to overweight (n = 64,498, 46.70%), from normal to obese (n = 21,259, 15.39%), and from overweight to obese (n = 4,371, 3.16%) were associated with a decreased risk of NSCLC (hazard ratio [HR] for trend = 0.78, P < 2×10-16). An MR study using BMI trajectory associated with genetic variants revealed no significant association between BMI trajectories and NSCLC risk. Further analysis of PRS showed that a higher GWAS-identified PRS (PRSGWAS) was associated with an increased risk of NSCLC, while the interaction between BMI trajectories and PRSGWAS with the NSCLC risk was not significant (PsPRS= 0.863 and PwPRS= 0.704). In GWIA analysis, four independent susceptibility loci (P < 1×10-6) were found to be associated with BMI trajectories on NSCLC risk, including rs79297227 (12q14.1, located in SLC16A7, Pinteraction = 1.01×10-7), rs2336652 (3p22.3, near CLASP2, Pinteraction = 3.92×10-7), rs16018 (19p13.2, in CACNA1A, Pinteraction = 3.92×10-7), and rs4726760 (7q34, near BRAF, Pinteraction = 9.19×10-7). Functional annotation demonstrated that these loci may be involved in the development of NSCLC by regulating cell growth, differentiation, and inflammation. CONCLUSIONS: Our study has shown an association between BMI trajectories, genetic factors, and NSCLC risk. Interestingly, four novel genetic loci were identified to interact with BMI trajectories on NSCLC risk, providing more support for the aetiology research of NSCLC. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov , NCT01696968 .

Prediction of acute kidney injury after cardiac surgery: model development using a Chinese electronic health record dataset.

BACKGROUND: Acute kidney injury (AKI) is a major complication following cardiac surgery that substantially increases morbidity and mortality. Current diagnostic guidelines based on elevated serum creatinine and/or the presence of oliguria potentially delay its diagnosis. We presented a series of models for predicting AKI after cardiac surgery based on electronic health record data. METHODS: We enrolled 1457 adult patients who underwent cardiac surgery at Nanjing First Hospital from January 2017 to June 2019. 193 clinical features, including demographic characteristics, comorbidities and hospital evaluation, laboratory test, medication, and surgical information, were available for each patient. The number of important variables was determined using the sliding windows sequential forward feature selection technique (SWSFS). The following model development methods were introduced: extreme gradient boosting (XGBoost), random forest (RF), deep forest (DF), and logistic regression. Model performance was accessed using the area under the receiver operating characteristic curve (AUROC). We additionally applied SHapley Additive exPlanation (SHAP) values to explain the RF model. AKI was defined according to Kidney Disease Improving Global Outcomes guidelines. RESULTS: In the discovery set, SWSFS identified 16 important variables. The top 5 variables in the RF importance matrix plot were central venous pressure, intraoperative urine output, hemoglobin, serum potassium, and lactic dehydrogenase. In the validation set, the DF model exhibited the highest AUROC (0.881, 95% confidence interval [CI] 0.831-0.930), followed by RF (0.872, 95% CI 0.820-0.923) and XGBoost (0.857, 95% CI 0.802-0.912). A nomogram model was constructed based on intraoperative longitudinal features, achieving an AUROC of 0.824 (95% CI 0.763-0.885) in the validation set. The SHAP values successfully illustrated the positive or negative contribution of the 16 variables attributed to the output of the RF model and the individual variable's effect on model prediction. CONCLUSIONS: Our study identified 16 important predictors and provided a series of prediction models to enhance risk stratification of AKI after cardiac surgery. These novel predictors might aid in choosing proper preventive and therapeutic strategies in the perioperative management of AKI patients.

Inhibition of N-Acetyltransferase 10 Suppresses the Progression of Prostate Cancer through Regulation of DNA Replication.

Cancer suppression through the inhibition of N-acetyltransferase 10 (NAT10) by its specific inhibitor Remodelin has been demonstrated in a variety of human cancers. Here, we report the inhibitory effects of Remodelin on prostate cancer (PCa) cells and the possible associated mechanisms. The prostate cancer cell lines VCaP, LNCaP, PC3, and DU145 were used. The in vitro proliferation, migration, and invasion of cells were measured by a cell proliferation assay, colony formation, wound healing, and Transwell assays, respectively. In vivo tumor growth was analyzed by transplantation into nude mice. The inhibition of NAT10 by Remodelin not only suppressed growth, migration, and invasion in vitro, but also the in vivo cancer growth of prostate cancer cells. The involvement of NAT10 in DNA replication was assessed by EdU labeling, DNA spreading, iPOND, and ChIP-PCR assays. The inhibition of NAT10 by Remodelin slowed DNA replication. NAT10 was detected in the prereplication complex, and it could also bind to DNA replication origins. Furthermore, the interaction between NAT10 and CDC6 was analyzed by Co-IP. The altered expression of NAT10 was measured by immunofluorescence staining and Western blotting. Remodelin markedly reduced the levels of CDC6 and AR. The expression of NAT10 could be altered under either castration or noncastration conditions, and Remodelin still suppressed the growth of in vitro-induced castration-resistant prostate cancers. The analysis of a TCGA database revealed that the overexpression of NAT10, CDC6, and MCM7 in prostate cancers were correlated with the Gleason score and node metastasis. Our data demonstrated that Remodelin, an inhibitor of NAT10, effectively inhibits the growth of prostate cancer cells under either no castration or castration conditions, likely by impairing DNA replication.

Correction to: Remodelin, an inhibitor of NAT10, could suppress hypoxia-induced or constitutional expression of HIFs in cells.

The article "Remodelin, an inhibitor of NAT10, could suppress hypoxia-induced or constitutional expression of HIFs in cells", written by "Yaqian Wu, Yanan Cao, Haijing Liu, Mengfei Yao, Ningning Ma and Bo Zhang", was originally published electronically on the publisher's internet portal https://link.springer.com/article/10.1007/s11010-020-03776-w on 11 June 2020 with open access. With the author(s)' decision to step back from Open Choice, the copyright of the article changed on 6 July 2020 to © Springer Science+Business Media, LLC, part of Springer Nature 2020 and the article is forthwith distributed under the terms of copyright. The original article has been corrected.

Remodelin, an inhibitor of NAT10, could suppress hypoxia-induced or constitutional expression of HIFs in cells.

Hypoxia-inducible factors (HIFs) are key mediators expressed under hypoxic condition and involved in many kinds of disease such as cancer and abnormal angiogenesis. Thus, development of their inhibitor has been extensively explored. Here, we describe a finding that Remodelin, a specific inhibitor of NAT10, could also inhibit the expression of HIFs. The presence of Remodelin could suppress the elevated level of HIF-1α protein and its nuclear translocation induced by either treatment of cobalt chloride (CoCl2) or hypoxia in dose or time-dependent way. More importantly, Remodelin could also inhibit the constitutional expression of HIF-1α and HIF-2α in VHL mutant 786-0 cells. With using of cells with depletion of NAT10 by shRNA or Crispr-Cas9 edited, we further demonstrated that inhibition of HIFs by Remodelin should need NAT10 activity. In biological analysis, the treatment of cultured HUVECs with Remodelin could inhibit in vitro cell migration and invasion and tube-formation. Our investigation implied that Remodelin could be a new potential inhibitor of HIFs for using in angiogenesis targeting therapy in either cancers or inflammatory diseases.

SnS2 /Co3 S4 Hollow Nanocubes Anchored on S-Doped Graphene for Ultrafast and Stable Na-Ion Storage.

SnS2 has been widely studied as an anode material for sodium-ion batteries (SIBs) based on the high theoretical capacity and layered structure. Unfortunately, rapid capacity decay associated with volume variation during cycling limits practical application. Herein, SnS2 /Co3 S4 hollow nanocubes anchored on S-doped graphene are synthesized for the first time via coprecipitation and hydrothermal methods. When applied as the anode for SIBs, the sample delivers a distinguished charge specific capacity of 1141.8 mAh g-1 and there is no significant capacity decay (0.1 A g-1 for 50 cycles). When the rate is increased to 0.5 A g-1 , it presents 845.7 mAh g-1 after cycling 100 times. Furthermore, the composite also exhibits an ultrafast sodium storage capability where 392.9 mAh g-1 can be obtained at 10 A g-1 and the charging time is less than 3 min. The outstanding electrochemical properties can be ascribed to the enhancement of conductivity for the addition of S-doped graphene and the existence of p-n junctions in the SnS2 /Co3 S4 heterostructure. Moreover, the presence of mesopores between nanosheets can alleviate volume expansion during cycling as well as being beneficial for the migration of Na+ .

Fabry-Pérot cavity-coupled microbolometer terahertz detector with a continuously tunable air spacer gap.

This Letter demonstrates tunable Nb5N6 microbolometers operating in the terahertz frequency range. An asymmetric-coupled Fabry-Pérot cavity is constituted by simply placing a movable metallic planar mirror in the back of the silicon substrate. The incident THz radiation onto the Nb5N6 microbolometer is effectively manipulated by changing the air spacer gap to modulate the phase relation between the reflected wave and incident wave. The experimental measurements reveal that the detailed evolution of the resonance bands as a function of spacing is in excellent agreement with the analysis by using interference theory and simulation. The results detail the design of THz detectors wherein a wide degree of tunability or a variable number of detection bands is desirable.

Mode of action of a novel anti-Listeria bacteriocin (CAMT2) produced by Bacillus amyloliquefaciens ZJHD3-06 from Epinephelus areolatus.

Bacteriocin CAMT2, produced by Bacillus amyloliquefaciens ZJHD3-06, has been shown to exhibit protective activity against important food spoilage and food-borne bacterial pathogens. This study was conducted to investigate the mode of action of bacteriocin CAMT2 against highly pathogenic Listeria monocytogenes ATCC 19111. The addition of bacteriocin CAMT2 at 64 AU/ml inhibited L. monocytogenes ATCC 19111. An efflux of K+ ions, lactic acid dehydrogenase and an increase in extracellular electrical conductivity was observed in CAMT2-treated L. monocytogenes. Electron microscopy showed morphological alterations such as uneven cell surface, accumulation of cell debris and bacterial lysis. These results show that bacteriocin CAMT2 inhibit L. monocytogenes by increasing cell permeability and inducing membrane damage, hence it has the great application potentials in ensuring food safety.

The nuclear GSK-3ß regulated post-transcriptional processing of mRNA through phosphorylation of SC35.

Glycogen synthase kinase-3ß (GSK-3ß) is a multifunctional serine/threonine kinase and regulates a variety of biological processes. Recent studies show GSK-3ß can regulate pre-mRNA processing and transcription through phosphorylation of multiple splicing factors, but the detailed mechanism is still undetermined. In this study, we further proved that GSK-3ß could specifically co-localize with SC35 in nuclear speckles depending on its kinase activity. Immunofluorescence and FISH studies showed the activity of nuclear GSK-3ß regulated the assembly of nuclear speckles and consequently modulated the post-transcriptional processing of mRNA. In addition, GSK-3ß phosphorylated SC35 and promoted its hyperphosphorylation, in which the unique C-terminal sequences were particularly important to efficiently sequential multiple phosphorylation of SC35. Hyperphosphorylated SC35 converged into cluster and lost its ability to perform splicing in nuclear speckles. More importantly, the nuclear GSK-3ß activity could be a part of Wnt/ß-catenin signaling activation by TCF4 and might take part in embryonic or tumorigenesis of cells.

A multifunctional supramolecular hydrogel: preparation, properties and molecular assembly.

A novel supramolecular hydrogel was designed and constructed by molecular self-assembly of a cationic gemini surfactant, 1,3-bis(N,N-dimethyl-N-cetylammonium)-2-propylacrylate dibromide (AGC16), and an anionic aromatic compound, trisodium 1,3,6-naphthalenetrisulfonate (NTS). Owing to its unique structure, the hydrogel (abbreviated as AGC16/NTS) has the potential to be used as a multifunctional drug delivery system. The structure and properties of AGC16/NTS were characterized by rheological measurements, differential scanning calorimetry, variable-temperature 1H nuclear magnetic resonance, ultraviolet-visible spectroscopy, variable-temperature fluorescence emission spectroscopy, cryogenic scanning electron microscopy, transmission electron microscopy and X-ray diffraction methods. The rheological and DSC analysis results revealed that the gel AGC16/NTS was formed below 57 °C. It was found from UV-vis, fluorescence and 1H NMR spectroscopy characterization that aromatic π-π stacking and hydrophobic forces were indispensable to the formation of AGC16/NTS. The Cryo-SEM and TEM observation results indicated that gelators AGC16 and NTS self-assembled into one-dimensional fibers which further tightly intertwined to form a three-dimensional network structure. Based on the spectroscopic data and X-ray diffraction measurement results, a self-assembly model was proposed, helping to further understand the molecular self-assembly mechanism of AGC16/NTS. It was also found that the electrostatic force, hydrophobic force and π-π interaction were the three main driving forces for the gelation. The multiple non-covalent interactions between AGC16 and NTS endowed the hydrogel with excellent performance when the hydrogel was used as a carrier for drug delivery, due to multiple micro-domains within the same gel system. We further investigated the encapsulation and releasing properties of the hydrogel, using the hydrophobic model drug curcumin (Cur) and the model drug naproxen sodium (Npx) with aromatic ring structure. The fluorescence spectroscopy analysis confirmed that Npx was carried through aromatic π-π stacking and the 1H NMR measurement result revealed that Cur was encapsulated within the hydrophobic cavities of AGC16/NTS through hydrophobic interaction. Moreover, the drug release study results showed a sustained release of drugs from the hydrogel, indicating good application prospects in exploring new multifunctional drug delivery systems.

Facile fabrication of Sudan red particle microcapsules by a polymerizable gemini surfactant and molecular assembly mechanisms.

An efficient method was developed to encapsulate water insoluble organic particles of Sudan red III (SR) in aqueous suspensions by using a polymerizable cationic gemini surfactant, 1,3-bis(N,N-dimethyl-N-cetylammonium)-2-(propylacrylate dibromide) (AGC16). The AGC16 coated SR microcapsules (AGC16@SR) were prepared by absorption of AGC16 on the surface of SR, followed by in situ homopolymerization (PAGC16). Several measurements, including transmission and scanning electron microscopy, isothermal titration calorimetry, zeta potential, electron paramagnetic resonance and small angle X-ray scattering, were performed to determine the adsorption amount of AGC16, and the layer structures and the molecular assembly mechanism in the AGC16@SR and PAGC16@SR systems, respectively. For comparison purposes, the polymerizable cationic surfactant with one head group and a single alkyl chain, acryloyloxyethyl-N,N-dimethyl-N-cetylammonium bromide (referred to as ASC16), as well as the systems of ASC16@SR and PASC16@SR were also investigated in parallel. It was found that AGC16 molecules and their aggregates were simultaneously assembled into a shell layer, in which the saturated adsorption amount of AGC16 on SR is less than 1/2 that of ASC16, but the assembly layer of AGC16 is more hydrophobic with greater packing tightness compared with that of ASC16. It was also revealed that after in situ homopolymerization, the microcapsule shell becomes more compact. In the case of PAGC16@SR, the layers show higher surface roughness and irregularity compared with that of PASC16@SR. Moreover, the sustained release behavior of SR was also evaluated. The results revealed that PAGC16@SR performed well for SR controlled release, which was sorted by release performance as the following sequence: PAGC16@SR > AGC16@SR > PASC16@SR > ASC16@SR. Thus, the polymerizable cationic gemini surfactant holds substantial potential to be developed as an ideal candidate of soft matter to construct efficient controllable release systems.

Off-response in ASH neurons evoked by CuSO4 requires the TRP channel OSM-9 in Caenorhabditis elegans.

The off-response of ASH neurons had been overlooked until the microfluidic devices were introduced for in vivo imaging of neuronal activity in Caenorhabditis elegans. The mechanisms of ASH off-response were completely unknown. Here we monitored ASH off-response to CuSO4 stimulation by use of microfluidic device and genetically encoded calcium indicator (GECI) - Case12. We found ASH neurons exhibited a multiphasic response to 10 mM and 50 mM CuSO4 of 30-s stimulation duration. ASH off-responding to Cu(2+) had been dramatically reduced in goa-1, mod-5, trpa-1 and egl-8 mutants. Moreover, in osm-9 mutants ASH off-response was completely eliminated. Neuron-specific rescue of osm-9 in ASH neurons restored the off-response and the normal avoidance behavior in worms.

A new prognostic model based on gamma-delta T cells for predicting the risk and aiding in the treatment of clear cell renal cell carcinoma.

BACKGROUND: ccRCC is the prevailing form of RCC, accounting for the majority of cases. The formation of cancer and the body's ability to fight against tumors are strongly connected to Gamma delta (γδ) T cells. METHODS: We examined and analyzed the gene expression patterns of 535 individuals diagnosed with ccRCC and 72 individuals serving as controls, all sourced from the TCGA-KIRC dataset, which were subsequently validated through molecular biology experiments. RESULTS: In ccRCC, we discovered 304 module genes (DEGRGs) that were ex-pressed differentially and linked to γδ T cells. A risk model for ccRCC was constructed using 13 differentially DEGRGs identified through univariate Cox and LASSO regression analyses, which were found to be associated with prognosis. The risk model exhibited outstanding performance in both the training and validation datasets. The comparison of immune checkpoint inhibitors and the tumor immune microenvironment between the high- and low-risk groups indicates that immunotherapy could lead to positive results for low-risk patients. Moreover, the inhibition of ccRCC cell proliferation, migration, and invasion was observed in cell culture upon knocking down TMSB10, a gene associated with different types of cancers. CONCLUSIONS: In summary, we have created a precise predictive biomarker using a risk model centered on γδ T cells, which can anticipate clinical results and provide direction for the advancement of innovative targeted therapies.

Synthesis and photophysical properties of dinuclear N-heterocyclic carbene (NHC) copper(I) complexes and their application to photoluminescent light-emitting diodes and anti-counterfeiting.

Here, a series of dinuclear N-heterocyclic carbene (NHC) copper(I) complexes having 3,3'-(1,4-phenylenebis(methylene))bis(1-(pyridin-2-yl)-1H-imidazolylidene as bis-NHC ligand and bis[(2-diphenylphosphino)phenyl]ether (POP) as auxiliary ligand have been successfully prepared, and their photophysical properites were investigaged experimentally and theocitcally. The resulting complexes all exhibited intense green to yellow emission that originated from the thermally activated delayed fluorescence (TADF) with a high photoluminescence quantum yield of up to 0.67 and longer excited-state lifetimes on the microsecond time scale in the solid state. Green and yellow light-emitting diode (LED) devices based on Cu(I) complexes have successfully achieved good color rendering indices. Moreover, the anti-counterfeiting patterns and QR codes made of Cu(I) complexes have been applied to clothing, banknotes, books and glass plates with excellent anti-counterfeiting effects.

Associations of dietary magnesium intake with the risk of atherosclerotic cardiovascular disease and mortality in individuals with and without type 2 diabetes: A prospective study in the UK Biobank.

BACKGROUND: The association between dietary magnesium (Mg) intake and the risk of atherosclerotic cardiovascular disease (ASCVD) remains uncertain. We aimed to examine the associations of dietary Mg intake with the risk of ASCVD events and mortality in individuals with and without type 2 diabetes. METHODS: A total of 149,929 participants (4603 with type 2 diabetes) from the UK Biobank were included in the analyses. The hazard ratios (HRs) and 95 % confidence intervals (CIs) were estimated using Cox proportional hazard models. Furthermore, interactions of dietary Mg intake with type 2 diabetes status were examined on multiplicative and additive scales. RESULTS: During a median follow-up of 12.0 and 12.1 years, 7811 incident ASCVD events and 5000 deaths (including 599 ASCVD deaths) were documented, respectively. There were significantly negative associations between sufficient dietary Mg intake (equal to or greater than the recommended daily intake) and the risk of ASCVD incidence (HR 0.63 [95 % CI 0.49;0.82]), ASCVD mortality (0.45 [0.24;0.87]), and all-cause mortality (0.71 [0.52;0.97]) in participants with type 2 diabetes, whereas no significant association was observed in participants without type 2 diabetes (1.01 [0.94;1.09] for ASCVD incidence; 1.25 [0.93;1.66] for ASCVD mortality; 0.97 [0.88;1.07] for all-cause mortality). Multiplicative and additive interactions of dietary Mg intake with type 2 diabetes status were both observed. CONCLUSION: Sufficient dietary Mg intake was significantly associated with lower risks of ASCVD events and mortality in individuals with type 2 diabetes but not in those without type 2 diabetes. Our findings provide insight into the importance of dietary Mg intake for reducing modifiable cardiovascular burden in individuals with type 2 diabetes, which may inform future personalized dietary guidelines.

Spicy food consumption and risk of vascular disease: Evidence from a large-scale Chinese prospective cohort of 0.5 million people.

BACKGROUND: Spicy food consumption has been reported to be inversely associated with mortality from multiple diseases. However, the effect of spicy food intake on the incidence of vascular diseases in the Chinese population remains unclear. This study was conducted to explore this association. METHODS: This study was performed using the large-scale China Kadoorie Biobank (CKB) prospective cohort of 486,335 participants. The primary outcomes were vascular disease, ischemic heart disease (IHD), major coronary events (MCEs), cerebrovascular disease, stroke, and non-stroke cerebrovascular disease. A Cox proportional hazards regression model was used to assess the association between spicy food consumption and incident vascular diseases. Subgroup analysis was also performed to evaluate the heterogeneity of the association between spicy food consumption and the risk of vascular disease stratified by several basic characteristics. In addition, the joint effects of spicy food consumption and the healthy lifestyle score on the risk of vascular disease were also evaluated, and sensitivity analyses were performed to assess the reliability of the association results. RESULTS: During a median follow-up time of 12.1 years, a total of 136,125 patients with vascular disease, 46,689 patients with IHD, 10,097 patients with MCEs, 80,114 patients with cerebrovascular disease, 56,726 patients with stroke, and 40,098 patients with non-stroke cerebrovascular disease were identified. Participants who consumed spicy food 1-2 days/week (hazard ratio [HR] = 0.95, 95% confidence interval [95% CI] = [0.93, 0.97], P <0.001), 3-5 days/week (HR = 0.96, 95% CI = [0.94, 0.99], P = 0.003), and 6-7 days/week (HR = 0.97, 95% CI = [0.95, 0.99], P = 0.002) had a significantly lower risk of vascular disease than those who consumed spicy food less than once a week (Ptrend <0.001), especially in those who were younger and living in rural areas. Notably, the disease-based subgroup analysis indicated that the inverse associations remained in IHD (Ptrend = 0.011) and MCEs (Ptrend = 0.002) risk. Intriguingly, there was an interaction effect between spicy food consumption and the healthy lifestyle score on the risk of IHD (Pinteraction = 0.037). CONCLUSIONS: Our findings support an inverse association between spicy food consumption and vascular disease in the Chinese population, which may provide additional dietary guidance for the prevention of vascular diseases.

CD44 Is Associated with Poor Prognosis of ccRCC and Facilitates ccRCC Cell Migration and Invasion through HAS1/MMP9.

BACKGROUND: In many solid tumors, CD44 has been identified as a cancer stem cell marker as well as an important molecular in cancer progression and metastasis, making it attractive for potential therapeutic applications. However, our knowledge of the biological function and mechanism of CD44 in clear cell renal cell carcinoma (ccRCC) is limited. METHODS: In this study, the expression, prognostic values and functional enrichment analysis of CD44 in ccRCC were analyzed using public databases. Quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemical (IHC) assays were taken to detect CD44 expression in ccRCC tissues. The effects of CD44 on the proliferation, migration and invasion of ccRCC cells were investigated by gain-of-function and loss-of-function experiments. Subcutaneous models further confirmed the role of CD44 in tumor growth. The relationship between CD44, HAS1 and MMP9 was investigated to uncover the regulatory mechanism of CD44 in ccRCC. RESULTS: CD44 was significantly upregulated in ccRCC and associated with poor overall survival (OS). Based on the functional enrichment analysis and PPI network, we found that CD44 had associations with ECM interaction and focal adhesion pathway. Clinical ccRCC sample validation revealed that CD44 mRNA and protein expression were significantly increased in ccRCC tissues, and strong CD44 staining was observed in four metastatic ccRCC cases. In vitro experiments showed that CD44 overexpression promoted cell proliferation, migration and invasion. In vivo experiments also demonstrated that CD44 overexpression accelerated tumor formation in mice. Finally, we found that CD44 regulates the expression of HAS1 in ccRCC, which is essential for the secretion of MMP9 and cell migratory ability. CONCLUSION: The upregulation of CD44 mRNA and protein expressions in ccRCC is indicative of unfavorable clinical prognoses. The CD44/HAS1/MMP9 axis is believed to exert a significant influence on the regulation of ECM degradation and ccRCC metastasis.

TPM2 attenuates progression of prostate cancer by blocking PDLIM7-mediated nuclear translocation of YAP1.

BACKGROUND: Prostate cancer (PCa) is a common malignant tumor of the genitourinary system. Clinical intervention in advanced PCa remains challenging. Tropomyosins 2 (TPM2) are actin-binding proteins and have been found as a biomarker candidate for certain cancers. However, no studies have explored the role of TPM2 in PCa and its regulatory mechanism. METHODS: TPM2 expression was assessed in Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) PCa patient dataset. The effect of TPM2 on PCa progression was assessed in vitro and in vivo by quantifying proliferation, migration, invasion and tumor growth assays, and the mechanism of TPM2 in PCa progression was gradually revealed by Western blotting, immunoprecipitation, and immunofluorescence staining arrays. RESULTS: TPM2 was found to be severely downregulated in tumor tissues of PCa patients compared with tumor-adjacent normal tissues. In vitro experiments revealed that TPM2 overexpression inhibited PCa cell proliferation, invasion and androgen-independent proliferation. Moreover, TPM2 overexpression inhibited the growth of subcutaneous xenograft tumors in vivo. Mechanistically, this effect was noted to be dependent on PDZ-binding motif of TPM2. TPM2 competed with YAP1 for binding to PDLIM7 through the PDZ-binding motif. The binding of TPM2 to PDLIM7 subsequently inhibited the nuclear transport function of PDLIM7 for YAP1. YAP1 sequestered in the cytoplasm phosphorylated at S127, resulting in its inactivation or degradation which in turn inhibited the expression of YAP1 downstream target genes. CONCLUSIONS: This study investigated the role of TPM2, PDLIM7, and YAP1 in PCa progression and castration resistance. TPM2 attenuates progression of PCa by blocking PDLIM7-mediated nuclear translocation of YAP1. Accordingly, targeting the expression or functional modulation of TPM2, PDLIM7, or YAP1 has the potential to be an effective therapeutic approach to reduce PCa proliferation and prevent the progression of castration-resistant prostate cancer (CRPC).

Causal inference between rheumatoid arthritis and prostate cancer.

It is unclear if the association between rheumatoid arthritis (RA) and a higher risk of prostate cancer (Pca) reflects a causal relationship. We conducted a meta-analysis and used the Mendelian randomization method (MR) to evaluate the association between RA and Pca risk. A meta-analysis and subgroup analysis of the incidence of Pca in patients with RA was conducted. To determine whether genetically elevated RA levels were causally linked to Pca, two MR samples were employed. To eliminate gender-related bias, we conducted a stratified analysis of the GWAS data for RA by gender, specifically including 140,254 males. Additional MR analysis was also performed to determine potential confounding factors influencing the association between genetically susceptible RA and Pca. In total, 409,950 participants were enrolled in 20 trials to investigate the Pca risk in patients with RA. The meta-analysis suggested that RA was unrelated to the Pca risk (SIR = 1.072, 95% CI, 0.883-1.261). However, a subgroup analysis showed that low smoking rates might increase the Pca risk in patients with RA by 24%. The MR analysis showed that increased genetic susceptibility to RA was related to a high Pca risk (OR = 36.20, 95%CI = 1.24-1053.12, P = 0.037). The causality estimation of MR-Egger, Weighted mode, Simple mode, and Weighted median method were similar in direction and magnitude. Although our meta-analysis found no correlation between RA and Pca risk, MR analyses supported a causal relationship between genetic susceptibility to RA and increased prostate risk. Early attention to Pca risk in patients with RA may be important for improving prognosis and mortality in such patients. Further research is needed to determine the etiology of RA attributed to Pca and its underlying mechanisms.

ATAD2 promotes glycolysis and tumor progression in clear cell renal cell carcinoma by regulating the transcriptional activity of c-Myc.

Clear cell renal cell carcinoma (ccRCC) is a common malignant tumor of the urogenital tract. Given that ccRCC is often resistant to radiotherapy and traditional chemotherapy, the clinical treatment of patients with ccRCC remains a challenge. The present study found that ATAD2 was significantly upregulated in ccRCC tissues. In vitro and in vivo experiments showed that the inhibition of ATAD2 expression mitigated the aggressive phenotype of ccRCC. ATAD2 was also associated with glycolysis in ccRCC. Interestingly, we found that ATAD2 could physically interact with c-Myc and promote the expression of its downstream target gene, thereby enhancing the Warburg effect of ccRCC. Overall, our study emphasizes the role of ATAD2 in ccRCC. The targeted expression or functional regulation of ATAD2 could be a promising method to reduce the proliferation and progression of ccRCC.