Modification of metals and ligands in two-dimensional conjugated metal-organic frameworks for CO2 electroreduction: A combined density functional theory and machine learning study.

Electrochemical carbon dioxide reduction reaction (CO2RR) is a promising technology to establish an artificial carbon cycle. Two-dimensional conjugated metal-organic frameworks (2D c-MOFs) with high electrical conductivity have great potential as catalysts. Herein, we designed a range of 2D c-MOFs with different transition metal atoms and organic ligands, TMNxO4-x-HDQ (TM = Cr∼Cu, Mo, Ru∼Ag, W∼Au; x  = 0, 2, 4; HDQ = hexadipyrazinoquinoxaline), and systematically studied their catalytic performance using density functional theory (DFT). Calculation results indicated that all of TMNxO4-x-HDQ structures possess good thermodynamic and electrochemical stability. Notably, among the examined 37 MOFs, 6 catalysts outperformed the Cu(211) surface in terms of catalytic activity and product selectivity. Specifically, NiN4-HDQ emerged as an exceptional electrocatalyst for CO production in CO2RR, yielding a remarkable low limiting potential (UL) of -0.04 V. CuN4-HDQ, NiN2O2-HDQ, and PtN2O2-HDQ also exhibited high activity for HCOOH production, with UL values of -0.27, -0.29, and -0.27 V, respectively, while MnN4-HDQ, and NiO4-HDQ mainly produced CH4 with UL values of -0.58 and -0.24 V, respectively. Furthermore, these 6 catalysts efficiently suppressed the competitive hydrogen evolution reaction. Machine learning (ML) analysis revealed that the key intrinsic factors influencing CO2RR performance of these 2D c-MOFs include electron affinity (EA), electronegativity (χ), the first ionization energy (Ie), p-band center of the coordinated N/O atom (εp), the radius of metal atom (r), and d-band center (εd). Our findings may provide valuable insights for the exploration of highly active and selective CO2RR electrocatalysts.

Targeting oncogenic MAGEA6 sensitizes triple negative breast cancer to doxorubicin through its autophagy and ferroptosis by stabling AMPKα1.

Melanoma-associated antigen A6 (MAGEA6) is well known to have oncogenic activity, but the underlying mechanisms by which it regulates tumor progression and chemo-resistance, especially in triple-negative breast cancer (TNBC), have been unknown. In the study, the differential expression genes (DEGs) in TNBC tumor tissues and TNBC-resistant tumor tissues were analyzed based on TCGA and GEO datasets. MAGEA6, as the most significantly expressed gene, was analyzed by RT-qPCR, western blotting and immunohistochemistry assay in TNBC cell lines and tumor tissues. The potential mechanisms that influence chemo-resistance were also evaluated. Results displayed that MAGEA6 was highly expressed in TNBC and involved in drug resistance. MAGEA6 silencing enhanced the chemo-sensitivity of TNBC to doxorubicin (DOX) in vitro and in vivo, as determined by decreasing IC50 value, proliferation and invasion capacity, and triggering apoptosis. Mechanistically, it was shown that MAGEA6 depletion sensitized TNBC to DOX via regulating autophagy. Ubiquitination assay displayed that knockdown of MAGEA6 decreased the AMPKα1 ubiquitination, thereby elevating the levels of AMPKα1 and p-AMPKα in TNBC cells. Importantly, AMPK inhibitor (Compound C) can reduce the LC3II/I level induced by sh-MAGEA6, indicating that sh-MAGEA6 activated AMPK signaling through suppressing AMPKα1 ubiquitination and then facilitated autophagy in TNBC. Furthermore, we also observed that AMPK is required for SLC7A11 to regulate ferroptosis, and supported the crux roles of MAGEA6/AMPK/SLC7A11-mediated ferroptosis on modulating DOX sensitivity in TNBC cells. These findings indicated that targeting MAGEA6 can enhance the chemo-sensitivity in TNBC via activation of autophagy and ferroptosis; its mechanism involves AMPKα1-dependent autophagy and AMPKα1/SLC7A11-induced ferroptosis.

Multi-Omics Integrative Analyses Identified Two Endotypes of Hip Osteoarthritis.

(1) Background: Osteoarthritis (OA) is a heterogeneous disorder, and subgroup classification of OA remains elusive. The aim of our study was to identify endotypes of hip OA and investigate the altered pathways in the different endotypes. (2) Methods: Metabolomic profiling and genome-wide genotyping were performed on fasting blood. Transcriptomic profiling was performed on RNA extracted from cartilage samples. Machine learning methods were used to identify endotypes of hip OA. Pathway analysis was used to identify the altered pathways between hip endotypes and controls. GWAS was performed on each of the identified metabolites. Transcriptomic data was used to examine the expression levels of identified genes in cartilage. (3) Results: 180 hip OA patients and 120 OA-free controls were classified into three clusters based on metabolomic data. The combination of arginine, ornithine, and the average value of 7 lysophosphatidylcholines had an area under the curve (AUC) of 0.97 (95% CI: 0.96-0.99) to discriminate hip OA from controls, and the combination of γ-aminobutyric acid, spermine, aconitic acid, and succinic acid had an AUC of 0.96 (95% CI: 0.94-0.99) to distinguish two hip OA endotypes. GWAS identified 236 SNPs to be associated with identified metabolites at GWAS significance level. Pro-inflammatory cytokine levels were significantly different between two endotypes (all p < 0.05). (4) Conclusions: Hip OA could be classified into two distinct molecular endotypes. The primary differences between the two endotypes involve changes in pro-inflammatory factors and energy metabolism.

[Application of ARHGAP8 in Predicting the Efficacy of Neoadjuvant Chemotherapy for Locally Advanced Mid-Low Rectal Cancer].

Objective To analyze the sensitivity of ARHGAP8 in predicting the efficacy of neoadjuvant chemotherapy in the patients with locally advanced mid-low colorectal cancer and provide accurate evidence for the treatment of advanced colorectal cancer. Methods The differentially expressed gene ARHGAP8 was screened out by bioinformatics analysis.Cancer tissue and rectal tissue of 68 patients with primary rectal cancer were selected.The rectal cancer tissue samples and the rectal tissue samples were collected for clinical validation of ARHGAP8 expression by quantitative real-time PCR,Western blotting,and immunohistochemistry.The clinical and pathological features such as gender,age,tumor stage,differentiation degree,and pathological type of the patients were collected for functional validation.Forty-four patients with locally advanced mid-low rectal cancer who received neoadjuvant chemotherapy were selected for immunohistochemical examination of ARHGAP8 expression.The expression level of ARHGAP8 was compared between before and after chemotherapy and among different efficacy groups. Results The bioinformatics analysis revealed differences in the expression level of ARHGAP8 between the cancer tissue and rectal tissue (P<0.001).The expression level of ARHGAP8 was correlated with tumor stage (P=0.024),lymph node metastasis (P=0.007),and age (P=0.005).Quantitative real-time PCR results showed that the mRNA level of ARHGAP8 in the cancer tissue was higher than that in the rectal tissue (P<0.001).Western blotting and immunohistochemistry results demonstrated that the protein level of ARHGAP8 in the cancer tissue was higher than that in the rectal tissue (P=0.011).The expression of ARHGAP8 was correlated with tumor size (P=0.010) and pathological stage (P=0.005),while it showed no significant association with tumor differentiation degree,lymph node metastasis,liver metastasis,Ki-67,or microsatellite instability expression level.The 44 patients receiving neoadjuvant chemotherapy included 13,8,8,and 15 patients of tumor regression grades 0,1,2,and 3,respectively.Among them,65.91% (29/44) patients showed responses to the treatment.After neoadjuvant chemotherapy,the expression of ARHGAP8 in the cancer tissue was down-regulated in the patients who responded to the chemotherapy (P<0.001).The response rate in the patients with low protein level of ARHGAP8 was 92.86%,which was higher than that (53.33%) in the patients with high protein level of ARHGAP8 (P=0.033). Conclusion ARHGAP8 is highly expressed in the rectal cancer tissue.The patients with locally advanced mid-low rectal cancer and low ARHGAP8 expression are more sensitive to neoadjuvant chemotherapy with the XELOX protocol.ARHGAP8 can serve as a potential biomarker for the occurrence and development of rectal cancer and an important index for evaluating the efficacy of neoadjuvant chemotherapy with the XELOX protocol in the patients with locally advanced mid-low rectal cancer.

A unified evaluation descriptor for π-bridges applied to metalloporphyrin derivatives.

Establishing the structure of porphyrins with a A-π-D-π-A configuration is one of the effective strategies to maintain their dominance and compensate shortcomings through flexible changes in fragments. In this regard, π-bridges have attracted wide attention as a parameter affecting molecular backbones, electron transfer, energy levels, absorption, and other properties. However, the essence and influence of π-bridges have not yet been confirmed. In order to satisfy the requirements of intelligent application in molecular design, this study aimed to investigate the control effect of differences in π-bridge composition (thiophene and selenophene) and connection type (single bonds, ethylenic bonds and fused) on photoelectric performance. Y6 and PC61BM were used as acceptors to build donor/acceptor (D/A) interfaces and characterize the film morphology in three dimensions. Results showed that the essence of π-bridges involves a strong bridging effect (adjusting ability) between A and D fragments rather than highlighting its own nature. The large value could obtain high open circuit voltages (VOC), large separation and small recombination rates as well as stable and tight morphology. Therefore, adjusting ability is a unified descriptor for evaluating π-bridges, and it is an effective strategy to adjust material properties and morphology. This insight and discovery may provide a new evaluation descriptor for the screening and design of π-bridges.

Chiral Macrocycles for Enantioselective Recognition.

The efficient synthesis of chiral macrocycles with highly enantioselective recognition remains a challenge. We have addressed this issue by synthesizing a pair of chiral macrocycles, namely, R/S-BINOL[2], achieving total isolated yields of up to 62% through a two-step reaction sequence. These macrocycles are readily purified by column chromatography over silica gel without the need for chiral separation, thus streamlining the overall synthesis. R/S-BINOL[2] demonstrated enantioselective recognition toward chiral ammonium salts, with enantioselectivity (KS/KR) values reaching up to 13.2, although less favorable separations were seen for other substrates. R/S-BINOL[2] also displays blue circularly polarized luminescence with a |glum| value of up to 2.2 × 10-3. The R/S-BINOL[2] macrocycles of this study are attractive as chiral hosts in that they both display enantioselective guest recognition and benefit from a concise, high-yielding synthesis. As such, they may have a role to play in chiral separations.

Systemic contact dermatitis in a family: Case report.

BACKGROUND: Systemic contact dermatitis (SCD) is an allergic inflammatory skin disease. We report that 3 family members developed SCD after exposing to laundry detergent containing benzalkonium chloride, which is rare. SCD caused by benzalkonium chloride has been reported. However, Similar symptoms in the whole family caused by it have not been reported yet. In our case, a 36-year-old man was diagnosed as SCD, and his symptoms had not controlled after 7 days treatment, until he stopped dressing the clothes washed by the laundry detergent containing benzalkonium chloride. It was interesting that both his wife and the daughter developed SCD successively, and they have not exposed to any haptens besides the benzalkonium chloride in the laundry detergent. METHODS: Dermoscopic examination showed bright-red background, focal branching vessels and white scales. HE staining from the lesion revealed hyperkeratosis and parakeratosis, focal subcorneal microabscess, ocal hyperkeratosis, koilocyte in the epidermis, and erythrocyte extravasation, fibroplasia, hyaline degeneration and scattered aggregates of lymphocytes in the dermis. Then path test was performed 1 month after recovery with benzalkonium chloride 0.05% and 0.1% in petrolatum. RESULTS: Stop the laundry detergent containing benzalkonium chloride. The symptoms had controlled after they stopped the laundry detergent containing benzalkonium chloride. CONCLUSION: The case highlights that benzalkonium chloride with very low concentration and repeated exposure may be an active agent of SCD. It is of the utmost importance to pay close attention to patients presenting with similar symptoms within the family. A thorough examination of the medical history is essential to determine the underlying cause.

The Role of Terminal Fluorination on Energy Inversion in Organic Solar Cells.

Suppressing non-radiative energy loss (ΔE3) mediated by the triplet charge transfer state is crucial for high-performance organic solar cells (OSCs). Here, we decode the energy inversion through multi-scale theoretical simulations, which inhibit the formation of non-emissive triplet (T1) state. However, it is mystified by the system dependence. We first demonstrate a direct relationship of "the probability of Face-on orientation (PFace-on) is proportional to the probability of energy inversion (PEI)", which is related to the function of terminal fluorination. Through Pearson's correlation coefficient and machine learning model, the useful stacking structural parameters were obtained to clarify the effect of π-bridge group on the function of terminal fluorination. Based on the molecular descriptors established, we explain that the fluorination effect is beneficial to Face-on orientation and thus energy inversion due to the enhanced intermolecular coupling. But the π-bridge inhibits this coupling with the interfacial stacking configuration appearing more "TT_IC". This work provides a directional standard for promoting energy inversion to reduce ΔE3 for the high-performance OSCs.

Downregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia.

Lipoprotein lipase (LPL) hydrolyzes circulating triglycerides (TGs), releasing fatty acids (FA) and promoting lipid storage in white adipose tissue (WAT). However, the mechanisms regulating adipose LPL and its relationship with the development of hypertriglyceridemia are largely unknown. WAT from obese humans exhibited high PAR2 expression, which was inversely correlated with the LPL gene. Decreased LPL expression was also inversely correlated with elevated plasma TG levels, suggesting that adipose PAR2 might regulate hypertriglyceridemia by downregulating LPL. In mice, aging and high palmitic acid diet (PD) increased PAR2 expression in WAT, which was associated with a high level of macrophage migration inhibitory factor (MIF). MIF downregulated LPL expression and activity in adipocytes by binding with CXCR2/4 receptors and inhibiting Akt phosphorylation. In a MIF overexpression model, high-circulating MIF levels suppressed adipose LPL, and this suppression was associated with increased plasma TGs but not FA. Following PD feeding, adipose LPL expression and activity were significantly reduced, and this reduction was reversed in Par2-/- mice. Recombinant MIF infusion restored high plasma MIF levels in Par2-/- mice, and the levels decreased LPL and attenuated adipocyte lipid storage, leading to hypertriglyceridemia. These data collectively suggest that downregulation of adipose LPL by PAR2/MIF may contribute to the development of hypertriglyceridemia.

A hybridization-induced charge-transfer state energy arrangement reduces nonradiative energy loss in organic solar cells.

Here, we explain why the Energy Gap Law and the energy inversion related to the charge-transfer state have opposite effects on the trend of nonradiative energy loss of organic solar cells. The root is the existing condition of energy inversion. There is indeed a certain probability of energy inversion, but it will eventually be implicit or explicit as determined by the hybridization, which depends on the electron-withdrawing unit of the donor, giving rise to different stacking sites. The triplet-state hybridization leads to an explicit characteristic, while singlet-state hybridization leads to an implicit characteristic.

High expression levels of centromere protein O participates in cell proliferation of human ovarian cancer.

Ovarian cancer is a common malignant tumor in women, with a high mortality rate ranking first among gynecological tumors. Currently, there is insufficient understanding of the causes, pathogenesis, recurrence and metastasis of ovarian cancer, and early diagnosis and treatment still face great challenges. The sensitivity and specificity of existing ovarian cancer screening methods are still unsatisfactory. Centromere protein O (CENP-O) is a recently discovered structural centromere protein that is involved in cell death and is essential for spindle assembly, chromosome separation, and checkpoint signaling during mitosis. The abnormal high expression of CENP-O was detected in various tumors such as bladder cancer and gastric cancer, and it participates in the regulation of tumor cell proliferation. In this study, we detect the expression abundance of CENP-O mRNA in different ovarian cancer cells ( ES-2, A2780, Caov-3, OVCAR-3 and SK-OV-3). The biological function changes of cell proliferation and apoptosis were detected and the role of CENP-O in ovarian cancer cell proliferation and apoptosis was explored by knocking down the expression of CENP-O gene. The results showed that CENP-O gene was significantly expressed in 5 types of ovarian cancer cell lines. After knocking down the CENP-O gene, the proliferation and cloning ability of ovarian cancer cells decreased, and the apoptosis increased. This study indicates that CENP-O has the potential to be a molecular therapeutic target, and downregulating the expression of CENP-O gene can break the unlimited proliferation ability of cancer cells and promote their apoptosis, providing a foundation and new ideas for subsequent molecular mechanism research and targeted therapy.

Neurotrophin-3 Facilitates Stemness Properties and Associates with Poor Survival in Lung Cancer.

INTRODUCTION: Cancer stem cells (CSCs) shape the tumor microenvironment via neuroendocrine signaling and orchestrate drug resistance and metastasis. Cytokine antibody array demonstrated the upregulation of neurotrophin-3 (NT-3) in lung CSCs. This study aims to dissect the role of NT-3 in lung CSCs during tumor innervation. METHODS: Western blotting, quantitative reverse transcription-PCR, and flow cytometry were used to determine the expression of the NT-3 axis in lung CSCs. NT-3-knockdown and NT-3-overexpressed cells were derived lung CSCs, followed by examining the stemness gene expression, tumorsphere formation, transwell migration and invasion, drug resistance, soft agar colony formation, and in vivo tumorigenicity. Human lung cancer tissue microarray and bioinformatic databases were used to investigate the clinical relevance of NT-3 in lung cancer. RESULTS: NT-3 and its receptor tropomyosin receptor kinase C (TrkC) were augmented in lung tumorspheres. NT-3 silencing (shNT-3) suppressed the migration and anchorage-independent growth of lung cancer cells. Further, shNT-3 abolished the sphere-forming capability, chemo-drug resistance, invasion, and in vivo tumorigenicity of lung tumorspheres with a decreased expression of CSC markers. Conversely, NT-3 overexpression promoted migration and anchorage-independent growth and fueled tumorsphere formation by upregulating the expression of CSC markers. Lung cancer tissue microarray analysis revealed that NT-3 increased in patients with advanced-stage, lymphatic metastasis and positively correlated with Sox2 expression. Bioinformatic databases confirmed a co-expression of NT-3/TrkC-axis and demonstrated that NT-3, NT-3/TrkC, NT-3/Sox2, and NT-3/CD133 worsen the survival of lung cancer patients. CONCLUSION: NT-3 conferred the stemness features in lung cancer during tumor innervation, which suggests that NT-3-targeting is feasible in eradicating lung CSCs.

Prognostic value of lymphocytes in patients with breast cancer receiving radiotherapy after breast-conserving surgery: A post hoc analysis of a phase III randomized trial.

PURPOSE: To evaluate the prognostic value of peripheral lymphocyte count (PLC) in the breast cancer patients after breast-conserving surgery (BCS) with radiotherapy (RT). METHODS AND MATERIALS: This post hoc analysis was performed using data of 628 patients from a phase III, randomized controlled trial comparing hypofractionated RT (HFRT) with conventional fractionated RT (CFRT) after BCS. PLCs were obtained before, during, and after RT until the 1-year follow-up. The optimal cut-off PLCs were determined using the maxstat package in R. Survival rates were estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS: A total of 275 (46.1 %) patients developed lymphopenia during RT, among them, 17 (2.8 %) had grade 3 lymphopenia and no one developed grade 4 lymphopenia. With a median follow-up of 110.8 months, patients with pre-RT PLCs of < 1.77 × 109/L had a significantly lower 10-year breast cancer-specific survival (BCSS) rate (P = 0.013) and overall survival (OS) rate (P = 0.026). Patients with a nadir PLC of < 1.35 × 109/L had a significantly poorer 10-year OS rate (P = 0.048). Multivariate analysis showed that a pre-RT PLC of < 1.77 × 109/L was an independent factor influencing BCSS and OS, while the effect of the nadir PLC did not remain significant. Neither PLC nor lymphopenia recovery at post-RT 1, 3, and 6 months and 1 year was associated with survival. CONCLUSIONS: Radiation-induced lymphopenia in patients with breast cancer after BCS tends to be mild. The lower pre-RT PLC predicted poorer survival.

Inhibitory effect of phellodendrine on C48/80-induced allergic reaction in vitro and in vivo.

The incidence of allergic reactions has risen steadily in recent years, prompting growing interest in the identification of efficacious and safe natural compounds that can prevent or treat allergic diseases. Phellodendron amurense Rupr. has long been applied as a treatment for allergic diseases, whose primary component is phellodendrine. However, the efficacy of phellodendrine as a treatment for allergic diseases remains to be assessed. Mast cells are the primary effectors of allergic reactions, which are not only activated by IgE-dependent pathway, but also by IgE-independent pathways via human MRGPRX2, rat counterpart MRGPRB3. As such, this study explored the effect and mechanism of phellodendrine through this family receptors in treating allergic diseases in vitro and in vivo. These analyses revealed that phellodendrine administration was sufficient to protect against C48/80-induced foot swelling and Evans blue exudation in mice, and suppressed C48/80-induced RBL-2H3 rat basophilic leukemia cells degranulation, and ß-HEX, HIS, IL-4, and TNF-α release. Moreover, phellodendrine could reduce the mRNA expression of MRGPRB3 and responsiveness of MRGPRX2 by altering its structure. It was able to decrease Ca2+ levels, phosphorylation levels of CaMK, PLCß1, PKC, ERK, JNK, p38, and p65, and inhibit the degradation of IκB-α. These analyses indicate that berberine inhibits the activation of PLC and downregulates the release of Ca2+ in the endoplasmic reticulum by altering the conformation of MRGPRB3/MRGPRX2 protein, thereby inhibiting the activation of PKC and subsequently inhibiting downstream MAPK and NF-κB signaling, ultimately suppressing allergic reactions. There may thus be further value in studies focused on developing phellodendrine as a novel anti-allergic drug.

Body mass weighted prostate-specific antigen levels, new markers to predict locally advanced prostate cancer after prostatectomy.

BACKGROUND: Prostate-specific antigen (PSA) remains the most useful marker for screening, risk categorization, and follow-up in patients with prostate cancer. In the obese population, several studies have revealed that obesity may not only inversely interfere with the concentration of PSA, but also increase the risk of prostate cancer. Thus, we considered using the body mass weighted PSA levels, presented as serum PSA concentration multiplied by body weight or body mass index (BMI), instead of traditional PSA concentration, as potential markers to predict locally advanced prostate cancer after prostatectomy. METHODS: We retrospectively collected and analyzed data acquired from a single institute at which robot-assisted laparoscopic radical prostatectomy was performed. A total of 174 patients underwent radical prostatectomy, and the collected data included age, PSA level, body weight, BMI, and pathology results. RESULTS: A total of 174 patients were diagnosed with adenocarcinoma of the prostate by needle biopsy, and most (N = 165) were considered to have localized disease on preoperative multiparameter magnetic resonance imaging. After prostatectomy, 73% (N = 127) of the patients remained in the localized disease group (group A) and 27% (N = 47) of the patients were reclassified to the locally advanced prostate cancer (group B). The value of PSA was higher in group B (16.9 vs 11.2 ng/dL; p = 0.062), but there was no statistically significant difference between the two groups. After using the numerical values of PSA × body weight and PSA × BMI, a statistically significant difference emerged between the two groups ( p = 0.0198 in PSA × BW; p = 0.0110 in PSA × BMI). CONCLUSION: The body mass-weighted PSA levels, instead of the traditional PSA concentration, may be better markers for predicting non-organ-confined disease after surgery. It may also be useful in screening and risk categorization.

IL-12-Overexpressed Nanoparticles Suppress the Proliferation of Melanoma Through Inducing ICD and Activating DC, CD8+ T, and CD4+ T Cells.

Purpose: The drug resistance and low response rates of immunotherapy limit its application. This study aimed to construct a new nanoparticle (CaCO3-polydopamine-polyethylenimine, CPP) to effectively deliver interleukin-12 (IL-12) and suppress cancer progress through immunotherapy. Methods: The size distribution of CPP and its zeta potential were measured using a Malvern Zetasizer Nano-ZS90. The morphology and electrophoresis tentative delay of CPP were analyzed using a JEM-1400 transmission electron microscope and an ultraviolet spectrophotometer, respectively. Cell proliferation was analyzed by MTT assay. Proteins were analyzed by Western blot. IL-12 and HMGB1 levels were estimated by ELISA kits. Live/dead staining assay was performed using a Calcein-AM/PI kit. ATP production was detected using an ATP assay kit. The xenografts in vivo were estimated in C57BL/6 mice. The levels of CD80+/CD86+, CD3+/CD4+ and CD3+/CD8+ were analyzed by flow cytometry. Results: CPP could effectively express EGFP or IL-12 and increase ROS levels. Laser treatment promoted CPP-IL-12 induced the number of dead or apoptotic cell. CPP-IL-12 and laser could further enhance CALR levels and extracellular HMGB1 levels and decrease intracellular HMGB1 and ATP levels, indicating that it may induce immunogenic cell death (ICD). The tumors and weights of xenografts in CPP-IL-12 or laser-treated mice were significantly reduced than in controls. The IL-12 expression, the CD80+/CD86+ expression of DC from lymph glands, and the number of CD3+/CD8+T or CD3+/CD4+T cells from the spleen increased in CPP-IL-12-treated or laser-treated xenografts compared with controls. The levels of granzyme B, IFN-γ, and TNF-α in the serum of CPP-IL-12-treated mice increased. Interestingly, CPP-IL-12 treatment in local xenografts in the back of mice could effectively inhibit the growth of the distant untreated tumor. Conclusion: The novel CPP-IL-12 could overexpress IL-12 in melanoma cells and achieve immunotherapy to melanoma through inducing ICD, activating CD4+ T cell, and enhancing the function of tumor-reactive CD8+ T cells.

Development of a clinical nomogram for prediction of response to neoadjuvant chemotherapy in patients with advanced gastric cancer.

BACKGROUND: The efficacy of neoadjuvant chemotherapy (NAC) in advanced gastric cancer (GC) is still a controversial issue. AIM: To find factors associated with chemosensitivity to NAC treatment and to provide the optimal therapeutic strategies for GC patients receiving NAC. METHODS: The clinical information was collected from 230 GC patients who received NAC treatment at the Central South University Xiangya School of Medicine Affiliated Haikou Hospital from January 2016 to December 2020. Least absolute shrinkage and selection operator logistic regression analysis was used to find the possible predictors. A nomogram model was employed to predict the response to NAC. RESULTS: In total 230 patients were finally included in this study, including 154 males (67.0%) and 76 females (33.0%). The mean age was (59.37 ± 10.60) years, ranging from 24 years to 80 years. According to the tumor regression grade standard, there were 95 cases in the obvious response group (grade 0 or grade 1) and 135 cases in the poor response group (grade 2 or grade 3). The obvious response rate was 41.3%. Least absolute shrinkage and selection operator analysis showed that four risk factors significantly related to the efficacy of NAC were tumor location (P < 0.001), histological differentiation (P = 0.001), clinical T stage (P = 0.008), and carbohydrate antigen 724 (P = 0.008). The C-index for the prediction nomogram was 0.806. The calibration curve revealed that the predicted value exhibited good agreement with the actual value. Decision curve analysis showed that the nomogram had a good value in clinical application. CONCLUSION: A nomogram combining tumor location, histological differentiation, clinical T stage, and carbohydrate antigen 724 showed satisfactory predictive power to the response of NAC and can be used by gastrointestinal surgeons to determine the optimal treatment strategies for advanced GC patients.

Evaluating combustion kinetics and quantifying fuel-N conversion tendency of shoe manufacturing waste.

Combustion is an effective and cost-efficient thermochemical conversion method for solid waste, showing promise for the resource utilization of shoe manufacturing waste (SMW). However, SMW is generally composed of different components, which can lead to unstable combustion and excessive pollutant emissions, especially NOx. To date, combustion characteristics, reaction mechanism and fuel nitrogen (fuel-N) conversion of different SMW components remain unclear. In this work, the combustion behavior of typical SMW components combustion was investigated using Thermogravimetric coupled with Fourier transform infrared spectrum (TG-FTIR). A simplified single-step reaction mechanism was proposed according to the temperature interval to estimate reaction mechanism of SMW. Additionally, the relationship between fuel-N conversion tendency and fuel properties was established. The results indicate that the values for the comprehensive combustion performance index (S) and flammability index (C) range from 1.65 to 0.44 and 3.98 to 1.37, respectively. This demonstrates the significant variability in combustion behavior among different SMW components. Cardboard, leather and sponge have higher values of S and C, suggesting a better ignition characteristic and a stable combustion process. During the combustion of SMW, nitrogen oxides (NO and N2O) are the main nitrogen-containing compounds in the flue gases, with NO being the major contributor, accounting for over 82.97 % of the nitrogen oxides. NO has a negative correlation with nitrogen content, but it is opposite for N2O, HCN and NH3. Furthermore, the conversion of NO, N2O and NH3 is proportional to logarithmic values of O/N, while its conversion to HCN is proportional to logarithmic values of VM/N. These findings facilitate the prediction of the fuel-N conversion of solid waste combustion. This work might shed light on combustion optimization and in-situ pollutant emission control in solid waste combustion.

Genomic heterozygosity is associated with a lower risk of osteoarthritis.

BACKGROUND: Genomic heterozygosity has been shown to confer a health advantage in humans and play a protective role in complex diseases. Given osteoarthritis (OA) is a highly polygenic disease, we set out to determine if an association exists between OA and genomic heterozygosity. RESULTS: End-stage knee and hip OA patients and healthy controls were recruited from the Newfoundland and Labrador (NL) population. The Arthritis Research UK Osteoarthritis Genetics (arcOGEN) consortium database was utilized as a replication cohort. DNA was extracted from blood samples and genotyped. Individual rates of observed heterozygosity (HetRate) and heterozygosity excess (HetExcess) relative to the expected were mathematically derived, and standardized to a z-score. Logistic regression modeling was used to examine the association between OA and HetRate or HetExcess. A total of 559 knee and hip OA patients (mean age 66.5 years, body mass index (BMI) 33.7 kg/m2, and 55% females) and 118 healthy controls (mean age 56.4 years, BMI 29.5 kg/m2, and 59% female) were included in the NL cohort analysis. We found that OA had an inverse relationship with HetRate and HetExcess with odds ratios of 0.64 (95% CI: 0.45-0.91) and 0.65 (95% CI: 0.45-0.93) per standard deviation (SD), respectively. The arcOGEN data included 2,019 end-stage knee and hip OA patients and 2,029 healthy controls, validating our findings with HetRate and HetExcess odds ratios of 0.60 (95% CI: 0.56-0.64) and 0.44 (95% CI: 0.40-0.47) per SD, respectively. CONCLUSIONS: Our results are the first to clearly show evidence, from two separate cohorts, that reduced genomic heterozygosity confers a risk for the future development of OA.