UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate cancer.

The role of tumor-associated macrophages (TAMs), along with the regulatory mechanisms underlying distinct macrophage activation states, remains poorly understood in prostate cancer (PCa). Herein, we report that PCa growth in mice with macrophage-specific Ubc9 deficiency is substantially suppressed compared with that in wild-type littermates, an effect partially ascribed to the augmented CD8+ T cell response. Biochemical and molecular analyses revealed that signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of the UBC9 inhibitor 2-D08 promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade therapy. Together, our results demonstrate that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs by promoting STAT4-mediated macrophage activation and macrophage-CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.

Transarterial chemoembolization plus apatinib with or without camrelizumab for unresected hepatocellular carcinoma: A two-center propensity score matching study.

Purpose: To compare the effectiveness and safety of transarterial chemoembolization (TACE) combined with apatinib and camrelizumab with those of TACE as well as apatinib among patients with unresectable hepatocellular carcinoma (HCC). Materials and methods: The data of patients with unresectable HCC (uHCC) who received TACE-apatinib-camrelizumab combination (TACE + AC group) and TACE-apatinib combination (TACE + A group) were collected from two centers between January 2018 and January 2022. Propensity score matching (PSM) was conducted to diminish the bias between the two groups. The primary outcome measures of the study were overall survival (OS) and progression-free survival (PFS), and the secondary outcome measures were response rate (ORR), disease control rate (DCR), and adverse events (AEs). Results: A total of 102 patients were enrolled in this study after PSM, with 34 patients in the TACE + AC group and 68 patients in the TACE + A group. Compared to the TACE + A group, TACE + AC had a significantly longer median OS (25.5 months, interquartile range [IQR], 23.5-33.0) than 18.5 months (IQR, 13.0-25.0; P = 0.001). Similarly, the PFS of the TACE + AC group was significantly improved (14.0 months, IQR, 9.0-NA) compared to that of the TACE + A group (5.0 months, IQR, 2.5-9.0; P = 0.001). The ORR rates (55.9% vs. 51.5%), and DCR rates (79.4% vs. 72.1%) were comparable between groups (P > 0.05). All treatment-related adverse events were tolerable and manageable, and no serious adverse events were observed. Conclusion: TACE combined with apatinib plus camrelizumab demonstrated superior efficacy to TACE plus apatinib for patients with unresectable HCC. The two combination therapies showed similar safety profiles.

Survival prediction for patients with malignant biliary obstruction caused by pancreatic cancer undergoing biliary drainage: the COMBO-PaS model.

BACKGROUND: Patients with pancreatic cancer-caused biliary obstruction (PC-BO) have poor prognosis, but we lack of tools to predict survival for clinical decision-making. This study aims to establish a model for survival prediction among patients with PC-BO. METHODS: A total of 172 patients with PC-BO treated with percutaneous biliary drainage were randomly divided into a training group (n = 120) and a validation group (n = 52). The independent risk factors for overall survival were selected to develop a Cox model. The predictive performance of M stage, hepatic metastases, cancer antigen 199, and the Cox model was determined. Naples prognostic score (NPS), the prognostic nutritional index (PNI), and the controlling nutritional status (CONUT) for 1-month mortality risk were compared with the Cox model. RESULTS: The Cox model was developed based on total cholesterol, direct bilirubin, hepatic metastases, cancer antigen 199, stenosis type, and preprocedural infection (all P < 0.05), which named "COMBO-PaS." The COMBO-PaS model had the highest area under the curves (AUC) (0.801-0.933) comparing with other predictors (0.506-0.740) for 1-, 3-, and 6-month survival prediction. For 1-month mortality risk prediction, the COMBO-PaS model had the highest AUC of 0.829 comparing with NPS, PNI, and CONUT. CONCLUSION: The COMBO-PaS model was useful for survival prediction among patients with PC-BO.

Biological Activities Underlying the Therapeutic Effect of Quercetin on Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic autoimmune disorder stemming from unrestrained immune activation and subsequent destruction of colon tissue. Genetic susceptibility, microbiota remodeling, and environmental cues are involved in IBD pathogenesis. Up to now, there are limited treatment options for IBD, so better therapies for IBD are eagerly needed. The therapeutic effects of naturally occurring compounds have been extensively investigated, among which quercetin becomes an attractive candidate owing to its unique biochemical properties. To facilitate the clinical translation of quercetin, we aimed to get a comprehensive understanding of the cellular and molecular mechanisms underlying the anti-IBD role of quercetin. We summarized that quercetin exerts the anti-IBD effect through consolidating the intestinal mucosal barrier, enhancing the diversity of colonic microbiota, restoring local immune homeostasis, and restraining the oxidative stress response. We also delineated the effect of quercetin on gut microbiome and discussed the potential side effects of quercetin administration. Besides, quercetin could serve as a prodrug, and the bioavailability of quercetin is improved through chemical modifications or the utilization of effective drug delivery systems. Altogether, these lines of evidence hint the feasibility of quercetin as a candidate compound for IBD treatment.

The Fra-1: Novel role in regulating extensive immune cell states and affecting inflammatory diseases.

Fra-1(Fos-related antigen1), a member of transcription factor activator protein (AP-1), plays an important role in cell proliferation, apoptosis, differentiation, inflammation, oncogenesis and tumor metastasis. Accumulating evidence suggest that the malignancy and invasive ability of tumors can be significantly changed by directly targeting Fra-1. Besides, the effects of Fra-1 are gradually revealed in immune and inflammatory settings, such as arthritis, pneumonia, psoriasis and cardiovascular disease. These regulatory mechanisms that orchestrate immune and non-immune cells underlie Fra-1 as a potential therapeutic target for a variety of human diseases. In this review, we focus on the current knowledge of Fra-1 in immune system, highlighting its unique importance in regulating tissue homeostasis. In addition, we also discuss the possible critical intervention strategy in diseases, which also outline future research and development avenues.

Arginine metabolism regulates the pathogenesis of inflammatory bowel disease.

The pathogenesis of inflammatory bowel disease (IBD) is related to genetic susceptibility, enteric dysbiosis, and uncontrolled, chronic inflammatory responses that lead to colonic tissue damage and impaired intestinal absorption. As a consequence, patients with IBD are prone to nutrition deficits after each episode of disease resurgence. Nutritional supplementation, especially for protein components, is often implemented during the remission phase of IBD. Notably, ingested nutrients could affect the progression of IBD and the prognostic outcome of patients; therefore, they should be cautiously evaluated prior to being used for IBD intervention. Arginine (Arg) is a semi-essential amino acid required for protein synthesis and intimately associated with gut pathophysiology. To help optimize arginine-based nutritional intervention strategies, the present work summarizes that during the process of IBD, patients manifest colonic Arg deficiency and the turbulence of Arg metabolic pathways. The roles of Arg-nitric oxide (catalyzed by inducible nitric oxide synthase) and Arg-urea (catalyzed by arginases) pathways in IBD are debatable; the Arg-polyamine and Arg-creatine pathways are mainly protective. Overall, supplementation with Arg is a promising therapeutic strategy for IBD; however, the dosage of Arg may need to be carefully tailored for different individuals at different disease stages. Additionally, the combination of Arg supplementation with inhibitors of Arg metabolic pathways as well as other treatment options is worthy of further exploration.

Aloperine Ameliorates IMQ-Induced Psoriasis by Attenuating Th17 Differentiation and Facilitating Their Conversion to Treg.

Aloperine is an anti-inflammatory compound isolated from the Chinese herb Sophora alopecuroides L. Previously, our group has reported that the generation of induced Treg was promoted by aloperine treatment in a mouse colitis model. However, the effect of aloperine on effector T cell subsets remains unclear. We therefore carefully examined the effect of aloperine on the differentiation of major subsets of T helper cells. Based on our results, psoriasis, a Th17 dominant skin disease, is selected to explore the potential therapeutic effect of aloperine in vivo. Herein, we demonstrated that topical application of aloperine suppressed epidermal proliferation, erythema, and infiltration of inflammatory cells in skin lesions. Mechanistic studies revealed that aloperine suppressed the differentiation of Th17 cells directly through inhibiting the phosphorylation of STAT3 or indirectly through impairing the secretion of Th17-promoting cytokines by dendritic cells. Moreover, aloperine enhanced the conversion of Th17 into Treg via altering the pSTAT3/pSTAT5 ratio. Collectively, our study supported that aloperine possesses the capacity to affect Th17 differentiation and modulates Th17/Treg balance, thereby alleviating imiquimod (IMQ)-induced psoriasis in mice.

SUMOylation of PDPK1 Is required to maintain glycolysis-dependent CD4 T-cell homeostasis.

The immune system is finely tuned to fight against infections, eradicate neoplasms, and prevent autoimmunity. Protein posttranslational modification (PTM) constitutes a molecular layer of regulation to guarantee the proper intensity of immune response. Herein, we report that UBC9-mediated protein SUMOylation plays an essential role in peripheral CD4 T-cell proliferation, but without a perceptible impact on T-cell polarization. Both conventional T-cell (Tcon) and regulatory T-cell (Treg) maintenance are differentially affected, which was likely caused by a shared deficit in cell glycolytic metabolism. Mechanistically, PDPK1 (3-phosphoinositide-dependent protein-kinase 1) was identified as a novel SUMOylation substrate, which occurred predominantly at lysine 299 (K299) located within the protein-kinase domain. Loss of PDPK1 SUMOylation impeded its autophosphorylation at serine 241 (S241), thereby leading to hypoactivation of downstream mTORC1 signaling coupled with incompetence of cell proliferation. Altogether, our results revealed a novel regulatory mechanism in peripheral CD4 T-cell homeostatic proliferation, which involves SUMOylation regulation of PDPK1-mTORC1 signaling-mediated glycolytic process.

GEO data mining and TCGA analysis reveal altered branched chain amino acid metabolism in pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor of the digestive system which has a less than 1% 5-year survival rate. The pathogenesis of PDAC development is incompletely understood. Genetic predisposition, disease history of chronic pancreatitis and diabetes elevate the risk of PDAC while environmental and dietary factors including smoking, alcohol abuse, high fat/protein intake as well as air pollution exacerbate PDAC progression. BCAAs, consisting of leucine, isoleucine and valine are essential amino acids that are obtained from food and play versatile roles in carcinogenesis. Recent studies have demonstrated that BCAA metabolism affects PDAC development but the results are controversial. To explore the possible engagement of BCAA metabolism in PDAC, we took advantage of the GEO and TCGA database and discovered that BCAA uptake is closely related to PDAC development while BCAA catabolism is down-regulated in PDAC tissue. Besides, NOTCH and MYC are differentially involved in BCAA metabolism in tumor and muscle, and enhanced lipid synthesis is independent of BCAA catabolism. Altogether, we highlight BCAA uptake as a promising target for PDAC treatment.

IRF/Type I IFN signaling serves as a valuable therapeutic target in the pathogenesis of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is an autoimmune disease characterized by unresolved colitis and epithelial injury. Intestinal microbiota and its interaction with immune system are critical etiologic factors. In response to gut virome and bacteria derived nucleic acid, interferon regulatory factors (IRFs) are activated to promote the production of cytokines, including type I interferons (IFN-Is), to help maintain intestinal homeostasis under both physiological and pathophysiological conditions. However, derailed IRF/IFN-I pathway other-wisely contributes to the progression of IBD with distinct IRF member exerting differential regulatory effect. Here, we summarize the recent advances regarding the role of IRF/IFN-I pathway in the development of IBD. We emphasize that IFN-I is a double-edged sword in IBD pathogenesis, as IFN-Is are protective in acute colitis while becoming pro-inflammatory during the chronic recovery phase. Besides, the functional outcome of IRFs is diverse and complex, which hinges on the cell types affected and the presence of other immune mediators. All in all, IRF/IFN-I pathway serves as a versatile regulator in IBD pathogenesis and holds the potential for therapeutic interventions.

Radiomics Facilitates Candidate Selection for Irradiation Stents Among Patients With Unresectable Pancreatic Cancer.

Purpose: To develop a model to select appropriate candidates for irradiation stent placement among patients with unresectable pancreatic cancer with malignant biliary obstruction (UPC-MBO). Methods: This retrospective study included 106 patients treated with an irradiation stent for UPC-MBO. These patients were randomly divided into a training group (74 patients) and a validation group (32 patients). A clinical model for predicting restenosis-free survival (RFS) was developed with clinical predictors selected by univariate and multivariate analyses. After integrating the radiomics signature, a combined model was constructed to predict RFS. The predictive performance was evaluated with the concordance index (C-index) in both the training and validation groups. The median risk score of progression in the training group was used to divide patients into high- and low-risk subgroups. Results: Radiomics features were integrated with clinical predictors to develop a combined model. The predictive performance was better in the combined model (C-index, 0.791 and 0.779 in the training and validation groups, respectively) than in the clinical model (C-index, 0.673 and 0.667 in the training and validation groups, respectively). According to the median risk score of 1.264, the RFS was significantly different between the high- and low-risk groups (p < 0.001 for the training group, and p = 0.016 for the validation group). Conclusions: The radiomics-based model had good performance for RFS prediction in patients with UPC-MBO who received an irradiation stent. Patients with slow progression should consider undergoing irradiation stent placement for a longer RFS.

Early Warning Models to Estimate the 30-Day Mortality Risk After Stent Placement for Patients with Malignant Biliary Obstruction.

PURPOSE: To develop, validate, and compare early warning models of the 30-day mortality risk for patients with malignant biliary obstruction (MBO) undergoing percutaneous transhepatic biliary stent placement (PTBS). MATERIALS AND METHODS: Between January 2013 and October 2018, this multicenter retrospective study included 299 patients with MBOs who underwent PTBS. The training set consisted of 166 patients from four cohorts, and another two independent cohorts were allocated as external validation sets A and B with 75 patients and 58 patients, respectively. A logistic model and an artificial neural network (ANN) model were developed to predict the risk of 30-day mortality after PTBS. The predictive performance of these two models was validated internally and externally. RESULTS: The ANN model had higher values of area under the curve than the logistic model in the training set (0.819 vs 0.797), especially in the validation sets A (0.802 vs 0.714) and B (0.732 vs 0.568). Both models had high accuracy in the three sets (75.9-83.1%). Along with a high specificity, the ANN model improved the sensitivity. The net reclassification improvement and integrated discrimination improvement also demonstrated that the ANN model led to improvements in predictive ability compared with the logistic model. CONCLUSIONS: Early warning models were proposed to predict the risk of 30-day mortality after PTBS in patients with MBO. The ANN model has higher accuracy and better generalizability than the logistic model.

A Systematic Review Exploring the Anticancer Activity and Mechanisms of Glucomannan.

Glucomannan, long recognized as the active ingredient of the traditional Chinese medicinal herb Konjac glucomannan, is a naturally occurring polysaccharide existing in certain plant species and fungi. Due to its special property to also serve as a dietary supplement, glucomannan has been widely applied in clinic to lower body weight and circulation cholesterol level and to treat constipation, diabetes, and arterial sclerosis. Besides the regulatory role engaged with gastroenterological and metabolic syndrome, recently, its therapeutic effect and the underlying mechanisms in treating cancerous diseases have been appreciated by mounting researches. The present review aims to emphasize the multifaceted aspects of how glucomannan exerts its anti-tumor function.

Risk Prediction for Early Biliary Infection after Percutaneous Transhepatic Biliary Stent Placement in Malignant Biliary Obstruction.

PURPOSE: To establish a nomogram for predicting the occurrence of early biliary infection (EBI) after percutaneous transhepatic biliary stent (PTBS) placement in malignant biliary obstruction (MBO). MATERIALS AND METHODS: In this multicenter study, patients treated with PTBS for MBO were allocated to a training cohort or a validation cohort. The independent risk factors for EBI selected by multivariate analyses in the training cohort were used to develop a predictive nomogram. An artificial neural network was applied to assess the importance of these factors in predicting EBI. The predictive accuracy of this nomogram was determined by concordance index (c-index) and a calibration plot, both internally and externally. RESULTS: A total of 243 patients (training cohort: n = 182; validation cohort: n = 61) were included in this study. The independent risk factors were length of obstruction (odds ratio [OR], 1.061; 95% confidence interval [CI], 1.013-1.111; P = .012), diabetes (OR, 5.070; 95% CI, 1.917-13.412; P = .001), location of obstruction (OR, 2.283; 95% CI, 1.012-5.149; P = .047), and previous surgical or endoscopic intervention (OR, 3.968; 95% CI, 1.709-9.217; P = .001), which were selected into the nomogram. The c-index values showed good predictive performance in the training and validation cohorts (0.792 and 0.802, respectively). The optimum cutoff value of risk was 0.25. CONCLUSIONS: The nomogram can facilitate the early and accurate prediction of EBI in patients with MBO who underwent PTBS. Patients with high risk (> 0.25) should be administered more effective prophylactic antibiotics and undergo closer monitoring.

Synthesis and Luminescence Properties of a Novel Yellow-White Emitting NaLa(MoO4)2: Dy3+, Li+ Phosphor.

Intense yellow-white NaLa(MoO4)2: Dy3+ phosphors co-doped with Li+ ions have been successfully synthesized via facile sol-gel combustion approach. The dependence of the crystal structure and crystallinity, particle morphology, photoluminescence property, fluorescent lifetime and absolute quantum efficiency of the as-prepared phosphors has been investigated. Stable yellow-white emission from 440 nm to 600 nm and higher absolute quantum efficiency were studied on Dy3+ doped NaLa(MoO4)2, Dy3+ and Li+ co-doped NaLa(MoO4)2, respectively. Surprisingly, only a small amount of Li+ can lead to a remarkable increase of the PL intensity and the quantum efficiency. Especially, along with 0.75 mol% Li+ ions induced in the NaLa(MoO4)2: Dy3+ phosphors, the absolute quantum efficiency increased from 13.8% to 22%, and the possible mechanism has been deeply discussed. Outstanding luminescence properties have certified that NaLa(MoO4)2: Dy3+, Li+ phosphors are promising candidates as new yellow-white components for optical devices.

Two new biflavonones from Coreopsis tinctoria.

Two new biflavonone compounds, sikokianin D (1) and sikokianin E (2), were isolated from the capitulum of Coreopsis tinctoria. The structures of these compounds were elucidated by spectroscopic techniques including NMR, HRESIMS and circular dichroism (CD).

Application of modified attapulgite in phthalate acid ester-contaminated soil: Effects on phthalate acid ester dissipation and the composition of soil microbial community.

The effects of modified attapulgite (MA) on the dissipations of the plasticizers di-n-butyl phthalate (DBP) and di-(2-ethylhexyl) phthalate (DEHP) in soil, as well as on the composition of soil microbial community, were studied. DBP, DEHP (50 mg kg(-1) in soil, respectively), and MA (1, 5, and 10 % in soil) were mixed thoroughly with soil and incubated for 60 days. DBP- and DEHP-contaminated soils without MA were used as the controls. Both of DBP and DEHP residues in bulk soils and four soil fractions were measured at five incubation times 1, 7, 15, 30, and 60 days, and their dissipation kinetic equations were analyzed. The microbial phospholipid fatty acid (PLFA) concentrations were also measured at the end of experiment. Our results showed that the effect of modified attapulgite on DBP dissipation was related to its dosage in soil. The DEHP dissipation was both inhibited by MA at the 5 and 10 % rates in soils. The application of MA changed the content percentages but did not change the concentration order of phthalate acid esters (PAEs) in soil particle-size fractions. The total microbial PLFA content was significantly increased by 5 and 10 % MA in the contaminated soils. Meanwhile, the gram-negative (GN)/gram-positive (GP) ratios increased when MA was applied at the dosages of 5 and 10 % in DBP and 10 % in DEHP-contaminated soils. Principal component analysis (PCA) indicated that the change of bacteria PLFA, especially the GN bacterial PLFA, depended on the dosages of MA added into soil. The application of MA into soil has a positive effect on reducing the eco-toxicity of PAEs in soil based on the analysis of the soil microbial PLFA.

Integrated photonics with programmable non-volatile memory.

Silicon photonics integrated circuits (Si-PIC) with well-established active and passive building elements are progressing towards large-scale commercialization in optical communications and high speed optical interconnects applications. However, current Si-PICs do not have memory capabilities, in particular, the non-volatile memory functionality for energy efficient data storage. Here, we propose an electrically programmable, multi-level non-volatile photonics memory cell (PMC) fabricated by standard complementary-metal-oxide-semiconductor (CMOS) compatible processes. A micro-ring resonator (MRR) was built using the PMC to optically read the memory states. Switching energy smaller than 20 pJ was achieved. Additionally, a MRR memory array was employed to demonstrate a four-bit memory read capacity. Theoretically, this can be increased up to ~400 times using a 100 nm free spectral range broadband light source. The fundamental concept of this design provides a route to eliminate the von Neumann bottleneck. The energy-efficient optical storage can complement on-chip optical interconnects for neutral networking, memory input/output interfaces and other computational intensive applications.

Biflavonoids from Caper (Capparis spinosa L.) fruits and their effects in inhibiting NF-kappa B activation.

Caper (Capparis spinosa L.) fruits have been widely used as food and folk medicine in the Mediterranean basin and in central and west Asia. In this study, two biflavonoids, isoginkgetin, and ginkgetin, together with three other flavonoids, were isolated from caper fruits. Their chemical structures were elucidated by spectroscopic analyses and comparison with literature. To our knowledge, isoginkgetin, ginkgetin and sakuranetin were identified in caper for the first time. Notably, it is also the first time that biflavonoids have ever been found in the Capparidaceae. Concentrations of the two biflavonoids were measured in caper fruits collected from four major growing areas in northwest China. The anti-inflammatory effects of the flavonoids from caper fruits were evaluated by secreted placental alkaline phosphatase (SEAP) reporter assay, which was designed to measure nuclear factor-kappa B (NF-κB) activation. Isoginkgetin and ginkgetin showed inhibitory effects in initial screen at 20 µM, while the effect of ginkgetin was much greater than that of isoginkgetin. In a dose-response experiment, the IC(50) value of ginkgetin was estimated at 7.5 µM, suggesting it could be a strong NF-κB inhibitor and worthy of study in vivo.