Combination therapy with PD-1 inhibition plus rapamycin and metformin enhances anti-tumor efficacy in triple negative breast cancer.

Immunotherapy using PD-1/PD-L1 inhibitors has been proved to be effective in triple negative breast cancer (TNBC), albeit only in a fraction of patients. Emerging evidences indicate mTOR blockade and metformin may re-orchestrate the immune system in tumors. Herein, in this study we aimed to evaluate the anti-tumor efficacy of PD-1 monoclonal antibody with mTOR inhibitor rapamycin or with the anti-diabetic drug metformin. The status of PD-1/PD-L1 and mTOR pathway was determined through analyzing the TCGA and CCLE data in TNBCs as well as by detection at mRNA and protein level. The inhibition of tumor growth and metastasis by anti-PD-1 combined with rapamycin or with metformin was evaluated in allograft mouse model of TNBC. The effects of combination therapy on the AMPK, mTOR and PD-1/PD-L1 pathways were also evaluated. The combination treatment with PD-1 McAb and rapamycin/metformin had additive effects on suppression of tumor growth and distant metastasis in mice. Compared with the control group and the monotherapy, combined PD-1 McAb with either rapamycin or metformin exhibited more obvious effects on induction of necrosis, CD8+ T lymphocytes infiltrating and inhibition of PD-L1 expression in TNBC homograft. In vitro study showed either rapamycin or metformin not only decreased PD-L1 expression, but increased p-AMPK expression and therefore led to down-regulation of p-S6. In summary, combination of PD-1 antagonist with either rapamycin or metformin led to more infiltrating TILs and decreased PD-L1 resulting in enhanced antitumor immunity and blockade of PD-1/PD-L1 pathway. Our results suggested such combination therapy may be a potential therapeutic strategy for TNBC patients.

Shatianyu dietary fiber (Citrus grandis L. Osbeck) promotes the production of active metabolites from its flavonoids during in vitro colonic fermentation.

BACKGROUND: Recent studies reveal that dietary fiber (DF) might play a critical role in the metabolism and bioactivity of flavonoids by regulating gut microbiota. We previously found that Shatianyu (Citrus grandis L. Osbeck) pulp was rich in flavonoids and DF, and Shatianyu pulp flavonoid extracts (SPFEs) were dominated by melitidin, obviously different from other citrus flavonoids dominated by naringin. The effects of Shatianyu pulp DF (SPDF) on the microbial metabolism and bioactivity of SPFEs is unknown. RESULTS: An in vitro colonic fermentation model was used to explore the effects of SPDF on the microbial metabolism and antioxidant activity of SPFEs in the present study. At the beginning of fermentation, SPDF promoted the microbial degradation of SPFEs. After 24 h-fermentation, the supplemented SPFEs were almost all degraded in SPFEs group, and the main metabolites detected were the dehydrogenation, hydroxylation and acetylation products of naringenin, the aglycone of the major SPFEs components. However, when SPFEs fermented with SPDF for 24 h, 60.7% of flavonoid compounds were retained, and SPFEs were mainly transformed to the ring fission metabolites, such as 3-(4-hydroxyphenyl) propionic acid, 3-phenylpropionic acid and 3-(3-hydroxy-phenyl) propionic acid. The fermentation metabolites of SPFEs showed stronger antioxidant activity than the original ones, with a further increase in SPDF supplemented group. Furthermore, SPFEs enriched microbiota participating in the deglycosylation and dehydrogenation of flavonoids, while co-supplementation of SPDF and SPFEs witnessed the bloom of Lactobacillaceae and Lactobacillus, contributing to the deglycosylation and ring fission of flavonoids. CONCLUSION: SDPF promote SPFEs to transform to active metabolites probably by regulating gut microbiota. © 2023 Society of Chemical Industry.

Loss of polarity protein Par3 in the intestinal epithelium promotes colitis-associated colorectal cancer progression by damaging tight junction assembly.

Partitioning defective 3 (Par3) is a polarity protein critical in establishing epithelial cell polarity and tight junctions (TJs). Impaired intestinal epithelial barrier integrity is closely associated with colitis-associated colorectal cancer (CRC) progression. According to the GEO and TCGA database analyses, we first observed that the expression of Par3 was reduced in CRC patients. To understand how Par3 is related to CRC, we investigated the role of Par3 in the development of CRC using an in vivo genetic approach. Our results show that the intestinal epithelium-specific PAR3 deletion mice demonstrated a more severe CRC phenotype in the context of azoxymethane/dextran sodium sulfate (AOM/DSS) treatment, with a corresponding increase in tumor number and inflammatory cytokines profile. Mechanistically, loss of Par3 disrupts the TJs of the intestinal epithelium and increases mucosal barrier permeability. The interaction of Par3 with ZO-1 prevents intramolecular interactions within ZO-1 protein and facilitates the binding of occludin to ZO-1, hence preserving TJs integrity. Our results suggest that Par3 deficiency permits pathogenic bacteria and their endotoxins to penetrate the intestinal submucosa and activate TLR4/MyD88/NF-κB signaling, promoting inflammation-driven CRC development and that Par3 may be a novel potential molecular marker for the diagnosis of early-stage CRC.

The prognostic significance of tumor-associated neutrophils and circulating neutrophils in glioblastoma (WHO CNS5 classification).

BACKGROUND: Tumor-associated neutrophils (TANs) in the tumor microenvironment are prognostic biomarkers in many malignancies. However, it is unclear whether TANs can serve as a prognostic marker for clinical outcomes in patients with glioblastoma (GBM), as classified according to World Health Organization Classification of Tumors of the Central Nervous System, fifth edition (CNS5). In the present study, we analyzed correlations of TANs and peripheral blood neutrophils prior to radiotherapy with overall survival (OS) in GBM (CNS5). METHODS: RNA-seq expression profiles of patients with newly diagnosed GBM (CNS5) were extracted from The Cancer Genome Atlas (TCGA), and The Chinese Glioma Genome Atlas (CGGA). TAN infiltration was inferred using CIBERSORTx algorithm. Neutrophil counts prior to radiotherapy in newly diagnosed GBM (CNS5) were obtained from the First Affiliated Hospital of Fujian Medical University. The prognostic value of TANs and peripheral blood neutrophils before radiotherapy was investigated using Kaplan-Meier analysis and Cox proportional hazards models. The robustness of these findings was evaluated by sensitivity analysis, and E values were calculated. RESULTS: A total of 146 and 173 individuals with GBM (CNS5) were identified from the TCGA and CGGA cohorts, respectively. High infiltration of TANs was of prognostic of poor OS in TCGA (HR = 1.621, 95% CI: 1.004-2.619) and CGGA (HR = 1.546, 95% CI: 1.029-2.323). Levels of peripheral blood neutrophils before radiotherapy (HR = 2.073, 95% CI: 1.077-3.990) were independently associated with poor prognosis. Sensitivity analysis determined that the E-value of high TANs infiltration was 2.140 and 2.465 in the TCGA and CGGA cohorts. CONCLUSIONS: TANs and peripheral blood neutrophil levels before radiotherapy are prognostic of poor outcomes in GBM (CNS5).

Six polymorphisms in the lncRNA H19 gene and the risk of cancer: a systematic review and meta-analysis.

BACKGROUND: Numerous studies have demonstrated long noncoding RNA (lncRNA) play an important role in the occurrence and progression of cancer, and single nucleotide polymorphisms (SNPs) located in lncRNA are considered to affect cancer suspensibility. Herein, a meta-analysis was carried out to better assess the relationship of H19 polymorphisms and cancer susceptibility. METHODS: A literature search was conducted through using PubMed, EMBASE, and Web of Science databases to obtain relevant publications before Aug 23, 2022. The reference lists of the retrieved studies were also investigated to identify additional relevant articles. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to appraise the risk of various cancers. RESULTS: There appeared to be a remarkable correlation between the rs2107425 variation and decreased cancer risk among Caucasians. Nevertheless, the rs217727 polymorphism was significantly associated with an increased risk of lung cancer, hepatocellular carcinoma and oral squamous cell carcinoma. Also, we found a significant correlation between the rs2839698 polymorphism and increased cancer risk among Asians, gastric cancer, hepatocellular carcinoma, hospital-based control and larger simple size subgroups, respectively. Similarly, the rs3741219 mutation was notably related to cancer risk in higher quality score. As for rs3024270 polymorphism, the homozygous model was markedly linked to cancer risk in overall analysis and population-based controls. There was no significant association between the rs3741216 polymorphism and cancer risk. CONCLUSION: H19 rs2839698 and rs3024270 were closely associated with overall cancer risk. H19 rs2107425 was related to lower cancer risk among Caucasians, while the rs2839698 was related to increased cancer risk among Asians. Our results supported that H19 SNPs were significantly correlated with cancer risk.

The psychological status in patients with nasopharyngeal carcinoma during radiotherapy.

PURPOSE: The psychological status of nasopharyngeal carcinoma (NPC) patients cannot be ignored. Few studies have studied the dynamic changes and influencing factors of psychological status in NPC patients during radiotherapy. The purpose of this study was to investigate the changing trends and risk factors of anxiety and depression in NPC patients during radiotherapy. METHODS: Demographic and clinical data of 232 newly treated NPC patients were collected. Before radiotherapy, the fourth week, and the end of radiotherapy were observational timepoints. Anxiety and depression states were evaluated by the hospital anxiety and depression scale. RESULTS: Scores of anxiety before radiotherapy, in the fourth week and at the end of radiotherapy were 6.32 ± 3.19, 7.87 ± 3.49, and 9.08 ± 3.69, respectively (P < 0.001). Incidence rates of anxiety were 34.0%, 55.1%, and 64.0% (P < 0.001). Depression scores were 5.31 ± 3.19, 7.07 ± 3.63, and 8.32 ± 3.89 (P < 0.001). Incidence rates of depression were 25.0%, 43.9%, and 56.0% (P < 0.001). Gender, age, education level, smoking, and treatment-related toxicity scores (P < 0.05) were independent risk factors for anxiety in patients with NPC during radiotherapy, while age, education level, and treatment-related toxicity scores (P < 0.05) were independent risk factors for depression in these patients. CONCLUSION: The incidence and degree of anxiety and depression in NPC patients increased during radiotherapy. Age, education level, and treatment-related side effects influenced anxiety and depression. More psychological nursing should be given to the NPC patients who are more likely to suffer from psychological distress.

Clinical characteristics of rehospitalized patients with COVID-19 in China.

This study aims to observe the clinical characteristics of recovered patients from Coronavirus Disease 2019 (COVID-19) with positive in reverse transcription-polymerase chain reaction (RT-PCR) or serum antibody. The profile, clinical symptoms, laboratory outcomes, and radiologic assessments were extracted on 11 patients, who tested positive for COVID-19 with RT-PCR or serum antibody after discharged and was admitted to Hubei No. 3 People's Hospital of Jianghan University for a second treatment in March 2020. The average interval time between the first discharge and the second admission measured 16.00 ± 7.14 days, ranging from 6 to 27 days. In the second hospitalization, one patient was positive for RT-PCR and serum antibody immunoglobulin M (IgM)-immunoglobulin G (IgG), five patients were positive for both IgM and IgG but negative for RT-PCR. Three patients were positive for both RT-PCR and IgG but negative for IgM. The main symptoms were cough (54.55%), fever (27.27%), and feeble (27.27%) in the second hospitalization. Compared with the first hospitalization, there were significant decreases in gastrointestinal symptoms (5 vs 0, P = .035), elevated levels of both white blood cell count (P = .036) and lymphocyte count (P = .002), remarkedly decreases in C-reactive protein and serum amyloid A (P < .05) in the second hospitalization. Additionally, six patients' chest computed tomography (CT) exhibited notable improvements in acute exudative lesions. There could be positive results for RT-PCR analysis or serum IgM-IgG in discharged patients, even with mild clinical symptoms, however, their laboratory outcomes and chest CT images would not indicate the on-going development in those patients.

NAS-HRIS: Automatic Design and Architecture Search of Neural Network for Semantic Segmentation in Remote Sensing Images.

The segmentation of high-resolution (HR) remote sensing images is very important in modern society, especially in the fields of industry, agriculture and urban modelling. Through the neural network, the machine can effectively and accurately extract the surface feature information. However, using the traditional deep learning methods requires plentiful efforts in order to find a robust architecture. In this paper, we introduce a neural network architecture search (NAS) method, called NAS-HRIS, which can automatically search neural network architecture on the dataset. The proposed method embeds a directed acyclic graph (DAG) into the search space and designs the differentiable searching process, which enables it to learn an end-to-end searching rule by using gradient descent optimization. It uses the Gumbel-Max trick to provide an efficient way when drawing samples from a non-continuous probability distribution, and it improves the efficiency of searching and reduces the memory consumption. Compared with other NAS, NAS-HRIS consumes less GPU memory without reducing the accuracy, which corresponds to a large amount of HR remote sensing imagery data. We have carried out experiments on the WHUBuilding dataset and achieved 90.44% MIoU. In order to fully demonstrate the feasibility of the method, we made a new urban Beijing Building dataset, and conducted experiments on satellite images and non-single source images, achieving better results than SegNet, U-Net and Deeplab v3+ models, while the computational complexity of our network architecture is much smaller.

Comparison of the Effects of Different Food-Grade Emulsifiers on the Properties and Stability of a Casein-Maltodextrin-Soybean Oil Compound Emulsion.

The improvement of food-grade emulsifiers in the properties and stability of complex emulsion has attracted much interest. In this study, the effects of six food-grade emulsifiers with a hydrophilic-lipophilic balance (HLB) range of 3.4-8.0 on a casein-maltodextrin-soybean oil compound emulsion were investigated by centrifugal precipitation rate (CPR), emulsifying activity index (EAI), microrheological properties, zeta potential, average particle size, and Turbiscan stability index (TSI). The optimal amounts of added succinylated monoglyceride (SMG) and polyglycerol fatty acid ester were 0.0025% and 0.1% (w/w), respectively, while that of the other four emulsifiers was 0.2% (w/w), according to the CPR. Thereinto, the SMG-stabilized emulsion exhibited the highest emulsifying activity and the lowest viscosity value and possessed the highest stability over 14 days of storage, which was indicated by the lowest TSI value and the smallest change in delta backscattering signal, relative to those of the other groups. Moreover, the emulsion stabilized by SMG displayed better emulsion stability than the control under a range of pH (6.0-8.0) and calcium ion concentrations (0-10 mM), which was attributed to the increased zeta potential value and the decreased average particle size of droplets with the addition of SMG. The present study provides a basic understanding for SMG improving the properties and stability of the complex emulsion.

Integrative analyses of genes associated with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), characterized by irreversible scarring and progressive destruction of the lung tissue, is one of the most common types of idiopathic interstitial pneumonia worldwide. However, there are no reliable candidates for curative therapies. Hence, elucidation of the mechanisms of IPF genesis and exploration of potential biomarkers and prognostic indicators are essential for accurate diagnosis and treatment of IPF. Recently, efficient microarray and bioinformatics analyses have promoted an understanding of the molecular mechanisms of disease occurrence and development, which is necessary to explore genetic alternations and identify potential diagnostic biomarkers. However, high false-positive rates results have been observed based on single microarray datasets. In the current study, we performed a comprehensive analysis of the differential expression, biological functions, and interactions of IPF-related genes. Three publicly available microarray datasets including 54 IPF samples and 34 normal samples were integrated by performing gene set enrichment analysis and analyzing differentially expressed genes (DEGs). Our results identified 350 DEGs genetically associated with IPF. Gene ontology analyses revealed that the changes in the modules were mostly enriched in the positive regulation of smooth muscle cell proliferation, positive regulation of inflammatory responses, and the extracellular space. Kyoto encyclopedia of genes and genomes enrichment analysis of DEGs revealed that IPF involves the TNF signaling pathway, NOD-like receptor signaling pathway, and PPAR signaling pathway. To identify key genes related to IPF in the protein-protein interaction network, 20 hub genes were screened out with highest scores. Our results provided a framework for developing new pathological molecular networks related to specific diseases in silico.

Characterization of saponins and phenolic compounds: antioxidant activity and inhibitory effects on α-glucosidase in different varieties of colored quinoa (Chenopodium quinoa Willd).

This study investigated the contents of saponins and phenolic compounds in relation to their antioxidant activity and α-glucosidase inhibition activity of 7 colored quinoa varieties. The total saponin content was significantly different among 7 varieties and ranged from 7.51 to 12.12 mg OAE/g DW. Darker quinoa had a higher content of phenolic compounds, as well as higher flavonoids and antioxidant activity than that of light varieties. Nine individual phenolic compounds were detected in free and bound form, with gallic acid and ferulic acid representing the major compounds. The free and bound phenolic compounds (gallic acid and ferulic acid in particular) exhibited high linear correlation with their corresponding antioxidant values. In addition, the free phenolic extracts from colored quinoa exhibited higher inhibitory activity against α-glucosidase than the bound phenolic extracts. These findings imply that colored quinoa with abundant bioactive phytochemicals could be an important natural source for preparing functional food.

Protein Kinase D was involved in vascular remodeling in spontaneously hypertensive rats.

The present study was designed to determine the role of PKD in vascular remodeling (VR) in Spontaneously hypertensive rats (SHRs). Increased SBP, VR and PKD activation were prominent in SHRs. The SBP has a positive correlation with the activation of PKD in SHRs. The ratio of media to lumen (MT/LD), volume fraction of collagen (VFC), hydroxyproline, IL-6, TNF-α and nitrotyrosine content were significantly related to the activated PKD. It may be concluded that PKD plays a central role in VR, and the mechanism may be related to its regulation of hypertrophy, fibrosis, inflammation and oxidative stress.

[Exploration of Domestic Medical Electrical Equipment Reliability Promotion Method].

The reliability of domestic medical equipment is one of the main factors that restrict the competitiveness of domestic medical devices. It is also an important factor that endangers the safety of patients and a blind spot in safety risk management. By analyzing the core elements of reliability and the situation of domestic medical device industry, this paper sorts out and analyzes the problems existing in the reliability of medical device industry, and puts forward the key points and problems to be solved to improve the reliability of domestic medical equipment products.

Laparoscopic intersphincteric resection with intraoperative radiotherapy using low-energy X-rays for locally advanced ultra-low rectal cancer.

BACKGROUND: In order to overcome the shortcomings of laparoscopic intersphincteric resection (Lap ISR), an alternative method of delivering intraoperative radiotherapy by Intrabeam X-rays radiotherapy system (XRS) is proposed in this paper. Intrabeam XRS is a device that uses low-energy X-rays source generated by a mobile controller unit, which is featured in accurate irradiation, reduced complications, and less exposure. The purpose of this study is to discuss the feasibility of Lap ISR with intra-operative radiotherapy using low-energy X-rays for locally advanced ultra-low rectal cancer in Asian woman. This novel proposed method will greatly increase the anus preserving probability and improved the quality of life. METHODS: A 53-year-old woman diagnosed with rectal adenocarcinoma had a strong desire to preserve the anal function and presented at the Jilin University Second Hospital, Jilin, China. The tumor's size was 4 cm × 3 cm. It was located 2 cm from the anus merge and invaded the levator ani muscle. Preoperative clinical staging was T4N1M0 and could be reached R0 resection. After the consent form was signed by the patient, Lap ISR combined with the applicator put through the anus (natural orifice) to the tumor bed was performed and prophylactic ileostomy synchronized the anastomosis. Patient only received 1-cycle chemotherapy regimen of oxaliplatin with capecitabine postoperatively due to personal reasons. Pre- or postoperative radiotherapy was not given. RESULTS: After clinical follow-up, until now, there is not any sign of local recurrence. Anus function and short-term complications are acceptable. The short-term effect is satisfying and we look forward to further assess the long-term effect. CONCLUSION: Laparoscopic intersphincteric resection with IORT using low-energy X-rays for the patients with late-stage ultra-low rectal cancer could provide an opportunity of preserving the anus function, and it is feasible for the selected patients. TRIAL REGISTRATION: Retrospectively registered; Trial registration: NCT03393234 ; Registered time: 05 January 2017.

Influence of Huang Lian Jie Du Decoction on Quorum Sensing System of Pseudomonas aeruginosa.

Context • Pseudomonas aeruginosa (P aeruginosa) is an opportunistic and nosocomial, Gram-negative pathogen that is characteristic of quorum sensing (QS) modulation. QS inhibition (QSI) is considered to be a new approach to antimicrobial treatment that may reduce issues of antibiotic resistance. Traditional Chinese herbs have been recognized as a source of QSI. Objective • This study was intended to investigate whether the Huang Lian Jie Du decoction (HLJJD) possesses the ability to produce anti-QS activity. Design • P aeruginosa PAO1 was cultivated in the presence and absence of HLJDD or of the aqueous extracts of each of its 4 constituent herbs: Rhizoma coptidis (RC), Radix scutellariae (RS), Cortex phellodendri (CP), and Fructus gardeniae jasminoidis (FGJ). The minimum inhibitory concentrations (MICs) were found for the HLJDD or its 4 constituents through testing each for evidence of antibacterial activity at 3.13, 6.25, 2.5, 25, 50, 100, 200, and 400 mg/mL. Outcome Measures • QS-dependent virulence factors were analyzed at subminimum MICs (sub-MICs) for the HLJDD and its constituent herbs. The mRNA of the QS genes was also assessed by a quantitative real-time polymerase chain reaction. Results • The HLJDD exhibited the lowest MIC of 100 mg/mL, compared with MICs of 200 mg/mL for the RC and RS, 400 mg/mL for the CP, and more than 400 mg/mL for the FGJ. At the sub-MIC of 50 mg/mL for HLJDD, the results showed a significant reduction in pyocyanin pigment, elastolytic activity, proteolytic activity, biofilm formation, and bacterial motilities in the PAO1, without inhibiting the bacterial growth. The mRNA level of the P aeruginosa elastase gene (lasB) was also significantly reduced. The mRNA analysis also showed an increasing tendency for overexpressed QS genes when observed at sub-MICs. That inhibitory tendency was also observed in the sub-MICs of the constituent herbs in different degrees. Conclusions • The HLJDD showed the synergism of its 4 constituents against the growth of P aeruginosa and the QS-dependent virulence factors. Its anti-QS activity may interrupt the QS domination of the virulence factors of P aeruginosa downstream, leading to the overexpressed QS genes.

Effect of Storage Conditions on Phenolic Profiles and Antioxidant Activity of Litchi Pericarp.

Changes of phenolic profiles and antioxidant activity of litchi pericarp during storage at 4 °C for seven days and at room temperature (RT) for 72 h were evaluated in this study. The contents of total phenolic and procyanidin decreased by 20.2% and 24.2% at 4 °C and by 37.8% and 47.8% at RT, respectively. Interestingly, the corresponding reductions of anthocyanins were 41.3% and 73%, respectively. Four phenolic compounds, including epicatechin, procyanidin A2, procyanidin B2, and quercetin-3-O-rutinoside-7-O-α-l-rhamnosidase were detected in litchi pericarp. Their contents after storage at 4 °C and at RT were decreased by 22.1⁻49.7% and 27.6⁻48.7%, respectively. The oxygen radical absorbance capacity (ORAC) and cellular antioxidant activity (CAA) of litchi pericarp decreased by 17.6% and 58.7% at 4 °C, and by 23.4% and 66.0% at RT, respectively. The results indicated that storage at 4 °C preserved more phenolics and retained higher antioxidant activity in litchi pericarp compared to storage at RT, suggesting that storage at 4 °C should be considered as a more effective method for slowing down the degradation of litchi pericarp phenolics.

A Comparison of the Chemical Composition, In Vitro Bioaccessibility and Antioxidant Activity of Phenolic Compounds from Rice Bran and Its Dietary Fibres.

The composition, in vitro bioaccessibility and antioxidant activities of the phenolic compounds in defatted rice bran (DRB) and its soluble and insoluble dietary fibres were systematically evaluated in this study. The total phenolic content of insoluble dietary fibre from DRB (IDFDRB) was much higher than that of the soluble dietary fibre from DRB (SDFDRB) but was 10% lower than that of DRB. Bound phenolics accounted for more than 90% of the total phenolics in IDFDRB, whereas they accounted for 34.2% and 40.5% of the total phenolics in DRB and SDFDRB, respectively. Additionally, the phenolic profiles and antioxidant activities were significantly different in DRB, SDFDRB and IDFDRB. The phenolic compounds in IDFDRB were much less bioaccessibility than those in DRB and SDFDRB due to the higher proportion of bound phenolics in IDFDRB. Considering that bound phenolics could be released from food matrices by bacterial enzymes in the large intestine and go on to exert significant beneficial health effects in vivo, further studies on IDFDRB are needed to investigate the release of the phenolics from IDFDRB via gut microbiota and the related health benefits.