Identification of ferroptosis-related subtypes, characteristics of TME infiltration and development of prognostic models in gastric cancer.

BACKGROUND: Ferroptosis is a distinct form of cell death characterized by unique morphology, biochemistry, and genetics, playing a crucial role in the initiation, progression, prognosis, and therapeutic strategies of tumors. However, the impact of ferroptosis-related genes (FRGs) on the tumor microenvironment (TME) remains unclear. This study may advance the existing knowledge of FRGs in gastric cancer, and push ahead with more effective prognostic assessment and the development of more effective immunotherapy approaches. METHODS: FRGs were acquired from the FerrDb database and a consensus clustering technique was adopted to categorize patients with GC into groups in line with the expression profiles of 44 FRGs in order to further investigate the expression properties of these proteins. Assessment of the immune status, microsatellite instability (MSI) and cancer stem cell (CSC) index between the high- and low- risk groups to assess the proportion of TIICs in the TME, ssGSVA was adopted to detect the abundance of infiltrating immune cells from the low-risk and high-risk groups. Expression levels of eight ferroptosis-related genes of prognostic signature in GC tissues and adjacent normal tissues was detected by RT-PCR. RESULTS: In the GC cohort, TP53 has the highest mutation frequency (44 %), and was shown to be highly linked with the expression levels of 11 FRGs. In accordance with the Kaplan-Meier curve, the overall survival time of patients with subtype A (Low FRG-score) discernibly exceeded that of patients with subtype B (High FRG-score).In addition, there is a significant difference in the infiltration of most immune cells between subtype A and subtype B, and some important immune checkpoints (CTLA4, PDCD1, CD274, LAG3, PDCD1LG2, and HAVCR2) have higher expression in cluster A. Finally, low FRG-scores were significantly associated with MSI-H status, while high FRG-scores were significantly associated with microsatellite stable status (MSS). FRG-score is negatively related to the cancer stem cell (CSC). CONCLUSION: Low FRG-score, due to its high microsatellite instability (MSI-H), high mutational load and immune activation, indicates the possible advantage of OS. In addition, the FRG-score was closely related to the cancer stem cell (CSC) index and the sensitive degree of chemotherapeutic drug.

Efficacy and safety of EGFR­TKIs plus Shenqi Fuzheng injection for non-small cell lung cancer patients with EGFR-sensitive mutations.

PURPOSE: The aim of this retrospective study is to evaluate the impact on efficacy and safety between epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) alone and in combination with Shenqi Fuzheng injection (SFI) in patients with advanced NSCLC harboring epidermal growth factor receptor (EGFR) activating mutations. METHODS: Retrospectively, information of 88 patients receiving EGFR-TKIs as first-line targeted treatment or in combination with SFI in the Affiliated Drum Tower Hospital of Nanjing University Medical College and the Affiliated Cancer Hospital of Anhui University of Science and Technology was collected. The primary endpoint was to assess progression-free survival (PFS) and safety of EGFR-TKIs alone or in combination with SFI. RESULTS: Between January 2016 and December 2019, a total of 88 patients were enrolled in this research, including 50 cases in the EGFR-TKIs single agent therapy group and 38 cases in the SFI combined with EGFR-TKIs targeted-therapy group. The median PFS (mPFS) of monotherapy group was 10.50 months (95%CI 9.81-11.19), and 14.30 months (95%CI 10.22-18.38) in the combination therapy group. Compared to the single EGFR-TKIs administration, combinational regimen with SFI exhibited a lower incidence of rash and diarrhea in patients and was even better tolerated. CONCLUSIONS: SFI combined with the first-generation EGFR-TKIs are more efficient, can prominently prolong the PFS and attenuate the adverse reactions in patients with advanced NSCLC with EGFR-sensitive mutations.

CXCR2 Is Essential for Radiation-Induced Intestinal Injury by Initiating Neutrophil Infiltration.

Neutrophils, known as an important part of the immune system, are the most abundant leukocyte population in peripheral blood, but excessive recruitment will lead to tissue/organ injury. RNA sequencing showed that ionizing radiation significantly increased the expression of characteristic genes of neutrophils in intestinal tissues compared with liver and lung tissues. By clearing neutrophils with an anti-Ly6G antibody, we found that neutrophil infiltration is critical for irradiation-induced intestinal injury. CXCR2 is a G-protein-coupled receptor that mediates the migration of neutrophils by combining with its ligands. Compared with observations in liver and lung tissues, we found that CXCR2 and its ligands, including CXCL1, CXCL2, CXCL3, and CXCL5, were all significantly upregulated in irradiated intestinal tissues. Further studies showed that SB225002, an inhibitor of CXCR2, could effectively inhibit the chemotaxis of neutrophils and tissue damage mediated by the CXCL-CXCR2 signalling pathway.

Phytotoxicity of atrazine combined with cadmium on photosynthetic apparatus of the emergent plant species Iris pseudacorus.

The combined pollution, instead of single pollution, has become a widespread contamination phenomenon in aquatic environment. However, little information is now available about the joint effects of the combined pollution, especially co-existed pesticides and heavy metals, on aquatic plants. In the present study, using continuous excitation chlorophyll fluorescence parameters and the OJIP transient, comparisons of herbicide atrazine (ATZ) phytotoxicity on Iris pseudacorus between in the presence and absence of cadmium (Cd) were evaluated over an exposure period of three weeks under laboratory conditions. Results showed that both ATZ and Cd were toxic to I. pseudacorus. The ratio Fv/Fo, specific electron transport energy (ET0/RC), and photochemistry efficiency (PIabs and PItotal) of this emergent plant species at individual ATZ and Cd concentrations were significantly lower than those of the control. ATZ mainly inhibited electron transport beyond QA at PSII acceptor side as indicated by the sharp rise of the J-step level of fluorescence rise kinetics. A pronounced K-step and the loss of I-step due to the damage on the OEC and PSI also occurred when ATZ was at or above 1.0 mg·L-1. In comparison to ATZ alone, ATZ combined with Cd resulted in a lower amplitude rise in J-step with apparent J-I and I-P phases; and significantly lower Fo with higher Fv/Fo, as well as greater ET0/RC with higher values of PIabs and PItotal. However, the adverse influences of ATZ combined with Cd on the above indicators were still significant as compared with the control. Therefore, the coexistence of Cd alleviated the individual phytotoxicities of ATZ, whereas combined pollution of ATZ and Cd still induced the decline in photosynthetic performance of I. pseudacorus, and its potential ecological impacts on the aquatic vegetation cannot be ignored. Our findings offer a better understanding of the joint effects of the pesticide and heavy metal on non-target aquatic plants, and provided valuable insights into the interaction of these pollutants in aquatic environment.

Reduced sensitivity to delayed time and delayed reward of the post-operative insular glioma patients in delay discounting.

Previous studies have shown that the insula is closely related to addiction, and the structure's role in delay discounting can be measured by a specific task, but the specific role of the insula has been less studied. In this study, we first conducted a lesion study in which we recruited healthy controls (n = 30) and patients with unilateral insula injury (n = 16) to complete a behavioral delay discounting task. Then we conducted a functional magnetic resonance imaging (fMRI) study, and a separate group healthy volunteers (n = 51) completed a delay discounting task during the fMRI scan. The lesion study showed a significant difference between the two groups in the delay discounting task, which revealed that insula injury was associated with impaired decision making. The fMRI study revealed choice-sensitive insula activation that was modulated by delayed time and delayed reward, indicating an important role of the insula in delay discounting. Overall, our results provide evidence for a role of the insular lobe in delay discounting and suggests that this structure may be considered an important factor in the future treatment and diagnosis of addiction disorders.

PPARα agonist fenofibrate relieves acquired resistance to gefitinib in non-small cell lung cancer by promoting apoptosis via PPARα/AMPK/AKT/FoxO1 pathway.

Recent studies show that intracellular accumulation of cholesterol leads to acquired resistance to gefitinib in non-small cell lung cancer (NSCLC) cells. In this study we investigated how to regulate the cholesterol levels in gefitinib-resistant NSCLC cells. We showed that intracellular cholesterol levels in gefitinib-resistant cell lines (PC-9/GR, H1975, H1650, and A549) were significantly higher than that in gefitinib-sensitive cell line (PC-9). Treatment with gefitinib (5 µM) significantly increased intracellular cholesterol levels in PC-9/GR, H1975, and H1650 cells. Gefitinib treatment downregulated the expression of PPARα, LXRα, and ABCA1, leading to dysregulation of cholesterol efflux pathway. We found that a lipid-lowering drug fenofibrate (20, 40 µM) dose-dependently increased the expression of PPARα, LXRα, and ABCA1, decreased the intracellular cholesterol levels, and enhanced the antiproliferative effects of gefitinib in PC-9/GR, H1975, and H1650 cells. We revealed that fenofibrate increased the gefitinib-induced apoptosis via regulating the key proteins involved in the intrinsic apoptosis pathway. In PC-9/GR, H1975 and H1650 cells, fenofibrate dose-dependently increased the expression of AMPK, FoxO1, and decreased the expression of AKT, which were remarkably weakened by knockdown of PPARα. In PC-9/GR cell xenograft mice, combined administration of gefitinib (25 mg · kg-1 · d-1) and fenofibrate (100 mg · kg-1 · d-1) caused remarkable inhibition on tumor growth as compared to treatment with either drug alone. All the results suggest that fenofibrate relieves acquired resistance to gefitinib in NSCLC by promoting apoptosis via regulating PPARα/AMPK/AKT/FoxO1 pathway. We propose that combination of gefitinib and fenofibrate is a potential strategy for overcoming the gefitinib resistance in NSCLC.

Association of Brain Metastases With Immune Checkpoint Inhibitors Efficacy in Advanced Lung Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: In pivotal immunotherapy trials, the efficacy of immune checkpoint inhibitors as treatments for lung cancer patients with brain metastases remains controversial. The aim of this study was to assess the relative efficacy of immunotherapy versus standard systemic therapy in advanced lung cancer patients with and without brain metastases. METHODS: Systematic searches of PubMed, Embase, Cochrane database, and conference proceedings up to Aug 6, 2020 without year and language restrictions. The main outcomes were the overall survival in patients with and without brain metastases measured by hazard ratios, and the difference in efficacy between patients with and without brain metastases was measured by ratio of hazard ratios. RESULTS: Nine eligible randomized controlled trials involving 6241 patients (682 [11%] with brain metastases and 5559 [89%] without brain metastases) were included in the analysis. A survival benefit of immunotherapy was observed for both patients with brain metastases (HR, 0.75; 95%CI, 0.53-0.97; P = .026) and patients without brain metastases (HR, 0.75; 95%CI, 0.67-0.83; P <.001). However, patients without brain metastases benefit more from immunotherapy than patients with brain metastases (HR, 1.37; 95%CI, 1.15-1.63; P = .001). Additionally, subgroup analyses indicated that tumor type affect the efficacy of immunotherapy in patients with brain metastases (HR, 1.04 vs 1.54; interaction, P = .041). CONCLUSIONS: Immunotherapy can significantly improve overall survival for advanced lung cancer patients with asymptomatic brain metastases, especially in patients with non-small-cell lung cancer, but the magnitude of benefit is brain metastases dependent. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020206597.

1,25-dihydroxyvitamin D3 signaling-induced decreases in IRX4 inhibits NANOG-mediated cancer stem-like properties and gefitinib resistance in NSCLC cells.

Recent studies have demonstrated that acquisition of cancer stem-like properties plays an essential role in promoting epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) resistance in non-small cell lung cancer (NSCLC); however, how to regulate cancer stem-like properties and EGFR-TKI resistance is largely unclear. In this study, we discovered that increased iroquois-class homeodomain protein 4 (IRX4) was related to gefitinib resistance in NSCLC cells. Knockdown of IRX4 inhibited cell proliferation, sphere formation, and the expression of CD133, ALDH1A1, NANOG, Sox2 and Notch1, and the transcriptional activity of NANOG promoter. IRX4 overexpression increased the protein level of NANOG and CD133 in PC-9 cells. Combination of knocking-down IRX4 with gefitinib increased cell apoptosis and decreased cell viability and the expression of p-EGFR and NANOG in PC-9/GR cells. IRX4 knockdown in a PC-9/GR xenograft tumor model inhibited tumor progression and the expression of NANOG and CD133 more effectively than single treatment alone. Knockdown of NANOG inhibited the expression of CD133 and restored gefitinib cytotoxicity, and NANOG overexpression-induced cancer stem-like properties and gefitinib resistance could be obviously reversed by knocking-down IRX4. Further, we found that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) reduced obviously the expression of IRX4 and NANOG by inhibiting the activation of TGF-ß1/Smad3 signaling pathway; moreover, combination of 1,25(OH)2D3 and gefitinib decreased cell viability and proliferation or tumor progression and the expression of IRX4 and NANOG compared with single treatment alone both in PC-9/GR cells and in a PC-9/GR xenograft tumor model. These results reveal that inhibition of IRX4-mediated cancer stem-like properties by regulating 1,25(OH)2D3 signaling may increase gefitinib cytotoxicity. Combination therapy of gefitinib and 1,25(OH)2D3 by targeting IRX4 and NANOG, could provide a promising strategy to improve gefitinib cytotoxicity.

[Effect and Mechanism of Attapulgite and Its Modified Materials on Bioavailability of Cadmium in Soil].

The effect of attapulgite (magnesium aluminium phyllosilicate) and its modified materials on the extractability of soil Cd and the accumulation of Cd in lettuce (Lactuca sativa) were investigated using a pot-culture experiment, and the immobilization mechanism of attapulgite and its modified materials was explored through X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The results showed that attapulgite and its modified materials could significantly reduce the Cd concentration in Lactuca sativa, with maximum reductions of 41.0% and 56.5%, respectively, and attapulgite modified materials treatments appeared more efficient than attapulgite treatments in reducing Cd uptake of Lactuca sativa. The saturated adsorption capacity for the adsorption of Cd2+ on attapulgite rose distinctly after being modified. Attapulgite and its modified materials could significantly reduce Cd content in soil CaCl2 extract at the dosage of 1%, with the maximum reduction rates of 34.2% and 34.3%, respectively. The attapulgite formed a complex to immobilize Cd mainly through the surface silanol and Cd2+ complexation reaction, while the modified attapulgite formed a complex mainly through the complexation of Cd2+ with carboxyl groups which existed in addition to the complexation with surface hydroxyl, thus reducing the mobility of Cd2+ and achieving remediation of Cd-contaminated soil. In summary, attapulgite and its modified materials can both be used for remediation of Cd-contaminated soil, and the mechanisms for this function were found to be different.

Sex determines which section of the SLC6A4 gene is linked to obsessive-compulsive symptoms in normal Chinese college students.

Previous case-control and family-based association studies have implicated the SLC6A4 gene in obsessive-compulsive disorder (OCD). Little research, however, has examined this gene's role in obsessive-compulsive symptoms (OCS) in community samples. The present study genotyped seven tag SNPs and two common functional tandem repeat polymorphisms (5-HTTLPR and STin2), which together cover the whole SLC6A4 gene, and investigated their associations with OCS in normal Chinese college students (N = 572). The results revealed a significant gender main effect and gender-specific genetic effects of the SLC6A4 gene on OCS. Males scored significantly higher on total OCS and its three dimensions than did females (ps < .01). The 5-HTTLPR in the promoter region showed a female-specific genetic effect, with the l/l and l/s genotypes linked to higher OCS scores than the s/s genotype (ps < .05). In contrast, a conserved haplotype polymorphism (rs1042173| rs4325622| rs3794808| rs140701| rs4583306| rs2020942) covering from intron 3 to the 3' UTR of the SLC6A4 gene showed male-specific genetic effects, with the CGAAGG/CGAAGG genotype associated with lower OCS scores than the other genotypes (ps < .05). These effects remained significant after controlling for OCS-related factors including participants' depressive and anxiety symptoms as well as stressful life events, and correction for multiple tests. These results are discussed in terms of their implications for our understanding of the sex-specific role of the different sections of the SLC6A4 gene in OCD.

Dissociation of subtraction and multiplication in the right parietal cortex: evidence from intraoperative cortical electrostimulation.

Previous research has consistently shown that the left parietal cortex is critical for numerical processing, but the role of the right parietal lobe has been much less clear. This study used the intraoperative cortical electrical stimulation approach to investigate neural dissociation in the right parietal cortex for subtraction and multiplication. Results showed that multiplication (as well as picture naming) was not affected by the cortical electrical stimulation on all the targeted sites of the right parietal cortex as well as those of the right temporal cortex. In contrast, stimulation at three right parietal sites (two sites in the right inferior parietal lobule and one in the right angular gyrus) impaired performance on simple subtraction problems. This study provided the first evidence from an intraoperative cortical electrical stimulation study to show the dissociation of arithmetic operations in the right parietal cortex. This dissociation between subtraction and multiplication suggests that the right parietal cortex plays a more significant role in quantity processing (subtraction) than in verbal processing (multiplication) in numerical processing.