Energy evolution mechanism of structural surfaces in sandstones with different dips based on the energy principle.

A uniaxial compression test was conducted on sandstone specimens at various inclination angles to determine the energy evolution characteristics during deformation and damage. Based on the principle of minimum energy dissipation, an intrinsic model incorporating the damage threshold was developed to investigate the mechanical properties of sandstone at different inclination angles, and the energy damage evolution during deformation and damage. This study indicated that when the inclination angle of the structural surface remained below 40°, sandstone exhibited varying mechanical properties based on different inclination angles. The peak strain was positively correlated with the inclination angle, whereas the compressive strength and modulus of elasticity showed negative correlations. From an energy perspective, the deformation and damage of sandstone under external loading entail processes of energy input, accumulation, and dissipation. Moreover, higher inclination angles of the structural surface resulted in a smaller absorbed peak strain and a reduced proportion of dissipated energy relative to the energy input, thereby affecting the evolution of energy damage throughout the process. As the inclination angle of the structural surface increased, the absorbed total strain at the peak value decreased, whereas the proportion of the dissipated energy increased. Additionally, the damage threshold and critical value of the rock specimens increased with the inclination angle. The critical value, a composite index comprising the peak strain, compressive strength, and elastic modulus, also increased accordingly. These findings can offer a novel perspective for analyzing geological disasters triggered by fissure zones within underground rock formations.

Preoperative neutrophil-to-lymphocyte ratio predicts symptomatic anastomotic leakage in elderly colon cancer patients: Multicenter propensity score-matched analysis.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), a composite inflammatory biomarker, is associated with the prognosis in patients with colorectal tumors. However, whether the NLR can be used as a predictor of symptomatic postoperative anastomotic leakage (AL) in elderly patients with colon cancer is unclear. AIM: To assess the role of the NLR in predicting the occurrence of symptomatic AL after surgery in elderly patients with colon cancer. METHODS: Data from elderly colon cancer patients who underwent elective radical colectomy with anastomosis at three centers between 2018 and 2022 were retrospectively analyzed. Receiver operating characteristic curve analysis was performed to determine the best predictive cutoff value for the NLR. Twenty-two covariates were matched using a 1:1 propensity score matching method, and univariate and multivariate logistic regression analyses were used to determine risk factors for the development of postoperative AL. RESULTS: Of the 577 patients included, 36 (6.2%) had symptomatic AL. The optimal cutoff value of the NLR for predicting AL was 2.66. After propensity score matching, the incidence of AL was significantly greater in the ≥ 2.66 NLR subgroup than in the < 2.66 NLR subgroup (11.5% vs 2.5%; P = 0.012). Univariate logistic regression analysis revealed statistically significant correlations between blood transfusion intraoperatively and within 2 d postoperatively, preoperative albumin concentration, preoperative prognostic nutritional index, and preoperative NLR and AL occurrence (P < 0.05); multivariate logistic regression analysis revealed that an NLR ≥ 2.66 [odds ratio (OR) = 5.51; 95% confidence interval (CI): 1.50-20.26; P = 0.010] and blood transfusion intraoperatively and within 2 d postoperatively (OR = 2.52; 95%CI: 0.88-7.25; P = 0.049) were risk factors for the occurrence of symptomatic AL. CONCLUSION: A preoperative NLR ≥ 2.66 and blood transfusion intraoperatively and within 2 d postoperatively are associated with a higher incidence of postoperative symptomatic AL in elderly patients with colon cancer. The preoperative NLR has predictive value for postoperative symptomatic AL after elective surgery in elderly patients with colon cancer.

CRISPR genome-wide screening identifies PAK1 as a critical driver of ARSI cross-resistance in prostate cancer progression.

Next-generation androgen receptor signaling inhibitors (ARSIs), such as enzalutamide (Enza) and darolutamide (Daro), are initially effective for the treatment of advanced prostate cancer (PCa) and castration-resistant prostate cancer (CRPC). However, patients often relapse and develop cross-resistance, which consequently makes drug resistance an inevitable cause of CRPC-related mortality. By conducting a comprehensive analysis of GEO datasets, CRISPR genome-wide screening results, ATAC-seq data, and RNA-seq data, we systemically identified PAK1 as a significant contributor to ARSI cross-resistance due to the activation of the PAK1/RELA/hnRNPA1/AR-V7 axis. Inhibition of PAK1 followed by suppression of NF-κB pathways and AR-V7 expression effectively overcomes ARSI cross-resistance. Our findings indicate that PAK1 represents a promising therapeutic target gene for the treatment of ARSI cross-resistant PCa patients in the clinic. STATEMENT OF SIGNIFICANCE: PAK1 drives ARSI cross-resistance in prostate cancer progression.

PVA/PAA/DMTD electrospun nanofibrous membrane for the selective adsorption of Pb(II) ions in liquid foods.

Lead (Pb(II)) contamination is common in liquid foods and can result from Pb(II) being present in the raw materials or during handling processes. However, due to the complexity of food matrices, there is limited data available concerning Pb(II) ion removal from food sources. This study focused on fabricating a PVA/PAA/DMTD electrospun nanofibrous membrane (ENFM) to efficiently and selectively remove Pb(II) ions from liquid foods. The PVA/PAA/DMTD ENFM had a maximum adsorption capacity of 138.3 mg/g for Pb(II) ions and demonstrated high selectivity toward the removal of Pb(II) ions. Negative values of the Gibbs free energy (ΔG°) showed that the spontaneous nature of the adsorption process was feasible at different temperatures. Moreover, it successfully removed Pb(II) ions from selected samples of commercially available drinks. Therefore, this adsorbent exhibits significant potential for removing Pb(II) ions from liquid food products, thereby reducing daily dietary exposure to Pb(II).

A nomogram for the prediction of survival for colorectal signet ring cell carcinoma after surgery: A population-based study.

The aim was to construct and verify a nomogram-based assessment of cancer-specific survival (CSS) in patients with colorectal signet ring cell carcinoma after surgery. Patients were collected from Surveillance, Epidemiology, and End Results program between 2004 and 2015. Independent prognostic indicators were determined in the training cohort by Cox regression model. We identified 2217 eligible patients, who were further categorized into the training set (n = 1693) as well as the validation set (n = 524). Multivariate analysis revealed that age at diagnosis, gender, grade, tumor size, T stage, N stage, and M stage were independent predictive indicators. Then, the above 7 predictive factors were incorporated into a nomogram model to assess CSS, which showed good calibration and discrimination capacities in both sets. Both internal and external calibration plot diagrams revealed that the actual results were consistent with the predicted outcomes. The time-independent area under the curves for 3-year and 5-year CSS in the nomogram were larger than American Joint Committee on Cancer and Surveillance, Epidemiology, and End Results summary stage system. Moreover, decision curve analysis indicated the clinical utility of the nomogram. The nomogram demonstrated favorable predictive accuracy of survival in colorectal signet ring cell carcinoma patients after surgery, which should be further confirmed before clinical implementation.

Mechanical characteristics and energy evolution in a rock mass with a weak structural plane.

The present aims to investigate the mechanical characteristics and energy evolution in rock masses containing weak structural planes under conventional triaxial loading conditions. Using a fluid-solid coupling test system of coal rock, numerous conventional triaxial compression tests were performed on rock masses at various dip angles of the structural plane. The obtained empirical outcomes revealed that the deviatoric stress-strain curve of the weak structural plane rock mass with an inclination angle greater than 20° rises step-by-step. On the macro level, slip-stability occurs on the upper and lower parts of the rock mass on the weak structural plane. Then mechanism of the slip-stability phenomenon is explored by analyzing the stress level in the rock mass with various inclination angles. It is found that the energy evolution during deformation and failure reflects the damaged state of the rock. Accordingly, the concept of 'slip dissipation energy' is proposed, and the values of each energy are calculated. The results have a good correspondence with the deviatoric stress-strain curve. Furthermore, it was found that the energy evolution of rock mass with a weak structural plane can be primarily classified into four stages, including storage of the initial energy, slip dissipation, abrupt increase in the pre-peak dissipation energy, and sudden drop in post-peak energy. Rock masses with various levels of dip angles exhibit similar elastic strain energy and dissipation energy at the peak point, demonstrating that energy evolution is dominated by energy storage and dissipation. At the same time, a negative correlation is observed between the structural plane dip angle and the occurrence of instantaneous impact instability failure in rock masses, indicating that a greater dip angle makes the rock mass less prone to experiencing instantaneous impact instability failure. This article provides a new idea for analyzing the geological disasters caused by external disturbances.

The transcription activity of OTX2 on p16 expression is significantly blocked by methylation of CpG shore in non-promoter of lung cancer cell lines.

Background: The aberrant expression of the classical tumor suppressor gene p16 is a frequent event in lung cancer mainly due to the hypermethylation of its 5'-cytosine-phosphate-guanine-3' island (Cgi). However, whether methylation happens in other regions and how p16 expression and function are affected are largely unknown. Methods: Clustered Regularly Interspaced Short Palindromic Repeats/dCas9 (CRISPR/dCas9) technology was used for methylation editing at specific site of p16. The effects of methylation editing were detected by 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium, inner salt (MTS), transwell migration and wound healing tests. Chromatin immnoprecipitation-quantitative polymerase chain reaction (CHIP-qPCR) was performed to explore the impact of Cgi shore methylation on the binding abilities of transcription factors (TFs) including YY1, SP1, ZNF148 and OTX2 to p16 gene. A rescue experiment was performed to verify the regulatory effect of OTX2 on p16. The negative relationship between p16 expression and the methylation level of Cgi shore in non-promoter region was further verified with datasets from The Cancer Genome Atlas (TCGA) program and lung adenocarcinoma (LUAD) patients' samples. Results: The suppressive effect of p16 Cgi shore methylation on its expression was demonstrated in both HEK293 and A549 cells using CRISPR/dCas9-mediated specific site methylation editing. Methylation of the Cgi shore in the p16 non-promoter region significantly decreased its expression and promoted cell growth and migration. The ability of OTX2 bound to p16 was significantly reduced by 19.35% after methylation modification. Over-expression of OTX2 in A549 cells partly reversed the inhibitory effect of methylation on p16 expression by 19.04%. The verification results with TCGA and LUAD patients' samples supported that the p16 Cgi shore is a key methylation regulatory region. Conclusions: Our findings suggested that methylation of the Cgi shore in the p16 non-promoter region can hamper the transcriptional activity of OTX2, leading to a reduction in the expression of p16, which might contribute to the development of lung cancer.

Development and validation of a nomogram to predict overall survival for cervical adenocarcinoma: A population-based study.

This study aimed to develop and validate a nomogram for predicting the overall survival of cervical adenocarcinoma (CAC) patients using a large database comprising patients with different ethnicities. We enrolled primary CAC cases with complete clinicopathological and survival data from the Surveillance, Epidemiology, and End Results program during 2004 to 2015. For training set samples, this work applied the Cox regression model to obtain factors independently associated with patient prognosis, which could be incorporated in constructing the nomogram. Altogether 3096 qualified cases were enrolled, their survival ranged from 0 to 155 (median, 45.5) months. As revealed by multivariate regression, age, marital status, tumor size, grade, International Federation of Gynecology and Obstetrics (FIGO) classification, pelvic lymph node metastasis, surgery, and chemotherapy served as the factors to independently predict CAC (all P < .05). We later incorporated these factors for constructing the nomogram. According to the concordance index determined, this nomogram had superior discrimination over FIGO classification system (all P < .001). Based on calibration plot, the predicted value was consistent with actual measurement. As revealed by time-independent area under the curves, our constructed nomogram had superior 5-year overall survival over FIGO system. Additionally, according to decision curve analysis, our constructed nomogram showed high clinical usefulness as well as favorable discrimination. Our constructed nomogram attains favorable performances, indicating that it may be applied in predicting survival for CAC patients.

Evaluating the Role of Morphological Parameters in the Prostate Transition Zone in PHI-Based Predictive Models for Detecting Gray Zone Prostate Cancer.

Background: The early detection of clinically significant prostate cancer (csPCa) through the integration of multidimensional parameters presents a promising avenue for improving survival outcomes for this fatal disease. This study aimed to assess the contribution of prostate transition zone (TZ) to predictive models based on the prostate health index (PHI), with the goal of enhancing early detection of csPCa in the prostate-specific antigen (PSA) gray zone. Methods: In this observational cross-sectional study, a total of 177 PSA gray zone patients (total prostate-specific antigen [tPSA] level ranging from 4.0 to 10.0 ng/mL) were recruited and received PHI detections from August 2020 to March 2022. Prostatic morphologies especially the TZ morphological parameters were measured by transrectal ultrasound (TRUS). Results: Univariable logistic regression indicated prostatic morphological parameters including total prostate volume (PV) indexes and transitional zone volume indexes were all associated with csPCa (P < .05), while the multivariable analysis demonstrated that C-reactive protein (CRP), PHI, PHI density (PHID), and PHI transition zone density (PHI-TZD) were the 4 independent risk factors. The receiver-operating characteristic (ROC) curve analysis suggested that integrated predictive models (PHID, PHI-TZD) yield area under the curves (AUCs) of 0.9135 and 0.9105 in csPCa prediction, which shows a relatively satisfactory predictive capability compared with other predictors. Moreover, the PHI-TZD outperformed PHID by avoiding 30 patients' unnecessary biopsies while maintaining 74.36% specificity at a sensitivity of 90%. Decision-curve analysis (DCA) confirmed the comparable performance of the multivariable full-risk prediction models, without the inclusion of the net benefit, thereby highlighting the superior diagnostic efficacy of PHID and PHI-TZD in comparison with other diagnostic models, in both univariable and multivariable models. Conclusion: Our data confirmed the value of prostate TZ morphological parameters and suggested a significant advantage for the TZ-adjusted PHI predictive model (PHI-TZD) compared with PHI and PHID in the early detection of gray zone csPCa under specific conditions.

Effect of intraoperative anastomotic reinforcement suture on the prevention of anastomotic leakage of double-stapling anastomosis for laparoscopic rectal cancer: a systematic review and meta-analysis.

BACKGROUND AND AIMS: The use of sutures to strengthen the anastomosis after rectal cancer surgery to reduce the possibility of anastomotic leakage has been debated. The aim of this systematic review and meta-analysis was to investigate the influence of intraoperative anastomotic reinforcing sutures on anastomotic leakage of double-stapling anastomosis for laparoscopic rectal cancer surgery. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane databases was performed to identify literature examining anastomotic leak as the primary outcome to compare studies of laparoscopic surgery for rectal cancer using the double-stapling anastomosis technique with or without intraoperative anastomotic reinforcement with sutures. RESULTS: A total of 1122 rectal cancer patients from 5 nonrandomized studies were included in the research. In the combined trial, intraoperative anastomotic reinforcement sutures significantly reduced the incidence of anastomotic leakage in patients who underwent laparoscopic rectal cancer surgery (OR, 0.32; 95% CI, 0.19-0.55; p < 0.0001). With or without intraoperative anastomotic reinforcing sutures, the incidence of postoperative reoperation for anastomotic leak did not differ substantially (OR, 0.32; 95% CI, 0.08-1.21, p = 0.09). Moreover, the surgery was prolonged due to anastomotic reinforcement with sutures (OR, 6.64; 95% CI, - 6.18 to 19.47, p = 0.31). CONCLUSIONS: Intraoperative anastomotic reinforcement with sutures may be associated with a lower incidence of anastomotic leakage. The amount of research evidence is limited because most of the studies analyzed did not include patients with factors such as neoadjuvant therapy or prophylactic stomas. Therefore, additional multicenter randomized controlled studies with larger size samples are needed to support the validity of the approach.

Loganin reduces diabetic kidney injury by inhibiting the activation of NLRP3 inflammasome-mediated pyroptosis.

Diabetic kidney disease (DKD) is an essential cause of end-stage renal disease. The ongoing inflammatory response in the proximal tubule promotes the progression of DKD. Timely and effective blockade of the inflammatory process to protect the kidney during DKD progression is a proven strategy. The purpose of this study was to investigate the protective effect of loganin on diabetic nephropathy in vivo and in vitro and whether this effect was related to the inhibition of pyroptosis. The results indicated that loganin reduced fasting blood glucose, blood urea nitrogen and serum creatinine concentrations, and alleviated renal pathological changes in DKD mice. In parallel, loganin downregulated the expression of pyroptosis related proteins in the renal tubules of DKD mice and decreased serum levels of interleukin-1beta (IL-1ß) and interleukin-18 (IL-18). Furthermore, in vitro experiments showed that loganin attenuated high glucose-induced HK-2 cell injury by reducing the expression of pyroptosis-related proteins, and cytokine levels were also decreased. These fundings were also confirmed in the polyphyllin VI (PPVI) -induced HK-2 cell pyroptosis model. Loganin reduces high glucose induced HK-2 cells pyroptosis by inhibiting reactive oxygen species (ROS) production and NOD-like receptor protein 3 (NLRP3) inflammasome activation. In conclusion, the inhibition of pyroptosis via inhibition of the NLRP3/Caspase-1/Gasdermin D (GSDMD) pathway might be an essential mechanism for loganin treatment of DKD.

Mucin2 regulated by Ho1/p38/IL-10 axis plays a protective role in polystyrene nanoplastics-mediated intestinal toxicity.

Micro/nano-plastics (MPs/NPs) are a newly discovered environmental pollutant that can be ingested by humans through food and drinking water. In this study we evaluated the impact of MPs/NPs on the intestinal barrier and its mechanism. Doses of MPs/NPs were used to treat Caco-2/HT29-MTX in-vitro model and in-vivo model. In in-vitro model, 20 nm polystyrene nanoplastics (PS-NPs) had higher cytotoxicity than larger particles (200 nm and 2000 nm), and led to the increase of the permeability along with the decreased expression of tight junction proteins. Intriguingly, 20 nm PS-NPs elevated the expression of MUC2 simultaneously. Further studies revealed that PS-NPs increased the expression of HO1 through ROS generation, and then activated p38 to elevate IL-10 secretion in Caco-2 cell. The IL-10 secreted by Caco-2 cell promoted the expression of MUC2 in HT29-MTX cell through STAT1/3. Elevated MUC2 expression alleviates the cytotoxicity of PS-NPs. Besides, increased intestinal permeability and up-regulation of MUC2 through Ho1/p38/IL-10 pathway was also observed in 20 nm PS-NPs treated mouse model. In conclusion, PS-NPs can induce the intestinal toxicity and result in the increased adaptive expression of MUC2 to resist this adverse effect. People with inadequate mucin expression need to pay more attention to the toxicity of PS-NPs. This study provided a valuable insight for clarifying the mechanism and potential risk of intestinal toxicity induced by nanoplastics.

Marital status is an independent prognostic factor for cervical adenocarcinoma: A population-based study.

Marriage has been reported as a beneficial factor associated with improved survival among cancer patients, but conflicting results have been observed in cervical adenocarcinoma (AC). Thus, this study is aimed to examine the relationship between the prognosis of cervical AC and marital status. Eligible patients were selected from 2004 to 2015 using the surveillance, epidemiology and end results (SEER) database. Cancer-specific survival (CSS) and overall survival (OS) were compared between married and unmarried groups. A total of 3096 patients had been identified, with married ones accounting for 51.29% (n = 1588). Compared to unmarried groups, more patients in the married group were relatively younger (aged ≤ 45) and belonged to white race, with grade I/II, Federation of International of Gynecologists and Obstetricians (FIGO) stage I/II and tumor size ≤4 cm. Apart from that, more patients received surgery, whereas fewer patients received chemotherapy and radiotherapy (all P < 0.05). The 5-year CSS and OS rates were 80.16% and 78.26% in married patients, 68.58% and 64.62% in the unmarried group (P < .0001). Multivariate analysis showed that marital status was an independent prognostic factor, and the married group performed better CSS (hazard ratio [HR]: 0.770; 95% confidence interval [CI]: 0.663-0.895; P = .001) as well as OS (HR: 0.751; 95%CI: 0.653-0.863; P < .001). As demonstrated by the results of subgroup analysis, married patients had better CSS and OS survival than unmarried ones in nearly all the subgroups. Marital status was identified as an independent prognostic factor for improved survival in patients with cervical AC.

Experimental and constitutive model study on the mechanical properties of a structural plane of a rock mass under dynamic disturbance.

An accurate description of the mechanical properties and deformation characteristics of a structural plane of a rock mass with a large chamber or slope under the ultimate stress with periodic stress disturbances is of great significance to ensure the stability and safety of underground rock engineering. By theoretically analysing the strength effect of a structural plane of a rock mass under dynamic disturbance, a criterion for the occurrence of shear damage on a structural plane of a compressed rock mass under dynamic disturbance is proposed. The results of the cyclic disturbance kinetic test show that there is a disturbance threshold for the shear failure of the structural plane under different disturbance stresses. When the disturbance stress is lower than the disturbance threshold, the cumulative plastic strain stabilizes with an increasing number of cycles; when the disturbance stress is higher than the disturbance threshold, an S-shaped curve of cumulative plastic strain versus the number of cycles is observed, revealing the progressive damage process and mechanism of such a rock structure plane under periodic dynamic disturbance. Based on perturbation concept theory, the relationship between the accumulated plastic strain and the number of cyclic loadings is similar to the relationship between strain and time, the creep curve. A new nonlinear viscous element is proposed, and the nonlinear element and the deformation element considering structural plane closure and sliding are combined with the Burgers model to form an 8-element nonlinear viscoelastic‒plastic creep constitutive model. Using the global optimization algorithm of 1stOpt, model validation and parameter identification are performed on the experimental data, and the results show that the model curve has a very good agreement with the experimental data. The model can accurately reflect the deformation characteristics of a structural plane of a rock mass under periodic dynamic disturbance. These research results provide a new idea for analysing disturbance-induced geohazards.

Dynamical changes of land use/land cover and their impacts on ecological quality during China's reform periods: A case study of Quanzhou city, China.

The rapid growth of China's economy has greatly accelerated the process of urbanization during China's reform periods. Urbanization has significantly caused land use and land cover (LULC) changes and thus has impacts on the local climate and ecosystem. This study chooses Quanzhou, a fast-developing city of southeast China, as an example to detect and quantify the LULC and ecological changes from 1989 to 2018 by using the remotely sensed technique. The LULC of Quanzhou was derived from the four Landsat images taken in 1989, 1999, 2007 and 2018, and the land-use-degree ratio index and land-use-change method were used to estimate the change of land use. The remote sensing based ecological index (RSEI) was used to detect the ecological changes of the city. The built-up land expansion intensity and annual built-up land expansion rate were carried out for seven districts of Quanzhou. The results show that the urban area of Quanzhou has drastically grown by 192.99 km2 at the expense of forest, water, and cropland land during the 1989~2018 period. Moreover, the built-up land of seven districts had expanded at the average rate of 0.027~0.154 per year and the built-up expansion intensity was higher than 0.59. The average RSEI value of Quanzhou city dropped from 0.78 in 1989 to 0.34 in 2018, which suggested an overall decline in ecological quality. The proportion of areas with an RSEI rating good decreased from 30.84% to 11.52% while the proportion of areas with rating bad increased from 4.73% to 19.11% during the past 29 years. This study has shown the built-up land expansion intensity is negatively correlated with the ecological quality change, and the increase in built-up land can greatly accelerate the decline of the ecological quality. Government policies play a profound impact on land use changes, urbanization and eco-environment changes. Therefore, the policy decision-makers should take enough action and consider integrating the concept of ecology to enable the healthy and sustainable development of the city.

Failure energy evolution of coal-rock combination with different inclinations.

In this paper, in the deformation and damage process under different confining pressures, the energy evolution characteristics and damage mechanism of coal-rock combinations with different inclination angles are studied. Based on the brittleness indexes of coal rock combinations, the evolution rules between brittleness indexes and the inclination are explored, as well as the confining pressure of coal rock combinations; then, the influence mechanism of the inclination angle of coal rock combinations on the plastic yielding degree, energy dissipation level, crack extension and fracture speed in the pre-peak stage is revealed. The composite specimens are mainly damaged due to oblique shear and accompanied by tensile damage; In the deformation and damage, various energies of coal rock composites are distributed as a negative exponential function of the inclination angle, which is significantly affected by the change of the confining pressure.

Serum multi-cytokines screening identifies TRAIL and IL-10 as probable new biomarkers for prostate health index diagnostic utility adjustment in grey zone aggressive prostate cancer detection: A single-center data in China.

Objective: To identify less invasive and easily applicable serum cytokine-derived biomarkers which contribute to the diagnostic utility and risk assessment ability of the prostate health index (PHI) based multivariable model in grey zone aggressive prostate cancer (AG PCa) early detection. Methods: Serum 45 cytokines screening was performed in a small training cohort consisting of 10 sera by Luminex liquid array-based multiplexed immunoassays and identified TRAIL and IL-10 as new biomarkers for PHI diagnostic utility adjustment for further validation with a multivariable predictive model in a cohort including 79 aggressive prostate cancer patients and 209 benign prostatic hyperplasia or indolent PCa patients within the PSA grey zone. Results: TRAIL and IL-10 were identified as potential serum biomarkers for AG PCa detection by the result of multi-cytokines screening in the univariate analysis, while multivariable logistic regression confirmed the AUC of the full risk predictive model (0.915) including tPSA, fPSA, PHI, TRAIL, and IL-10 was higher than various diagnostic strategies. DCA suggested a superior net benefit and indicated a good discriminative ability of the full risk model consistently with the result of the nomogram. Conclusion: We suggest a significant advantage for the PHI-based multivariate combinations of serum TRAIL and IL-10 comparing to PHI or other serum-derived biomarkers alone in the detection and risk stratification of grey zone AG PCa.

Tumor-associated macrophages promote migration and invasion via modulating IL-6/STAT3 signaling in renal cell carcinoma.

Tumor-associated macrophages (TAMs) promote tumor cell growth and metastasis in various human cancers. However, the role of TAMs in renal cell carcinoma (RCC) is rarely investigated. Herein, we observed that the infiltration of TAMs was obviously elevated in RCC tumor tissues, high infiltration of TAMs was closely associated with tumor progression and poor prognosis in RCC patients. In vitro assays further indicated that the conditioned medium of TAMs (TAMs CM) facilitated migration, invasion, and epithelial-mesenchymal transition (EMT) in RCC cells. Moreover, we found that IL-6 was involved in the functions of TAMs in RCC; IL-6 neutralizing antibody (IL-6NA) partly abolished the effect of TAMs on RCC cells. In addition, we demonstrated that TAMs might exert their roles by activating STAT3 signaling in RCC, and IL-6 was responsible for TAMs-induced STAT3 signaling activation. In conclusion, our results revealed that high infiltration of TAMs may promote RCC cells migration, invasion, and EMT via modulating IL-6/STAT3 signaling, further suggesting a potential of novel treatment strategies targeting TAMs or IL-6 for metastatic RCC.

Non-drug efflux function of ABCC5 promotes enzalutamide resistance in castration-resistant prostate cancer via upregulation of P65/AR-V7.

Drug resistance is responsible for castration-resistant prostate cancer (CRPC)-associated mortality. While ATP binding cassette subfamily C member 5 (ABCC5) has been reported to regulate multiple drug resistance, its drug-efflux function may not be the main reason underlying resistance to enzalutamide, an androgen receptor inhibitor. Here, we aimed to determine whether the non-drug efflux function of ABCC5 affects enzalutamide resistance. The ABCC5 expression data in patients with prostate cancer (PCa) were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus, and their correlation with disease prognosis was analyzed. Immunohistochemical staining was performed on a cohort of 80 patient samples. Proliferation of enzalutamide-resistant 22RV1 and C4-2B cells was investigated using CCK-8, EdU, and colony formation assays. The effect of ABCC5 silencing on enzalutamide resensitization was evaluated in vitro and in vivo. Functional assays indicated that ABCC5 depletion resensitized enzalutamide-resistant cells to inhibit cell growth and impeded xenograft tumor proliferation. Mechanistically, luciferase and ChIP assays confirmed that P65 regulated AR expression and activity by binding to its promoter, while ABCC5-mediated resistance effected by AR-V7 (one of the widely studied AR splicing variants that meditate AR antagonist resistance) upregulation could be reversed by P65 knockdown. Furthermore, activation of the NF-κB pathway reversed the effects of ABCC5 knockdown by extra AR-V7 expression. Thus, ABCC5 might be a novel target for enzalutamide-resistant CRPC treatment.

Modified Prostate Health Index Density Significantly Improves Clinically Significant Prostate Cancer (csPCa) Detection.

Background: Early screening of clinically significant prostate cancer (csPCa) may offer opportunities in revolutionizing the survival benefits of this lethal disease. We sought to introduce a modified prostate health index density (mPHI) model using imaging indicators and to compare its diagnostic performance for early detection of occult onset csPCa within the prostate-specific antigen (PSA) gray zone with that of PHI and PHID. Methods and Participation: Between August 2020 and January 2022, a training cohort of 278 patients (total PSA 4.0-10.0 ng/ml) who were scheduled for a prostate biopsy were prospectively recruited. PHI and PHID were compared with mPHI ( LD TRD × APD × TPV × PHI ) for the diagnosis performance in identifying csPCa. Pathology outcomes from systematic prostate biopsies were considered the gold standard. Results: This model was tested in a training cohort consisting of 73 csPCa, 14 non-clinically significant prostate cancer(non-csPCa), and 191 benign prostatic hyperplasia (BPH) samples. In the univariate analysis for the PSA gray zone cohort, for overall PCa, the AUC of mPHI (0.856) was higher than PHI (0.774) and PHID (0.835). For csPCa, the AUC of mPHI (0.859) also surpassed PHI (0.787) and PHID (0.825). For detection of csPCa, compared with lower specificities from PHI and PHID, mPHI performed the highest specificity (76.5%), by sparing 60.0% of unnecessary biopsies at the cost of missing 11 cases of csPCa. The mPHI outperformed PHI and PHID for overall PCa detection. In terms of csPCa, mPHI exceeds diagnostic performance with a better net benefit in decision curve analysis (DCA) compared with PHI or PHID. Conclusions: We have developed a modified PHI density (mPHI) model that can sensitively distinguish early-stage csPCa patients within the PSA gray zone. Clinical Trial Registration: ClinicalTrials.gov, NCT04251546.