Peripheral CD4+CD25hiCD127low regulatory T cells are increased in patients with gastrointestinal cancer.

BACKGROUND: Regulatory T cells (Tregs) play an important role in regulation of immune response and immunologic tolerance in cancer. Gastrointestinal cancer is still a leading cause of cancer-related death in the world. This study aimed to detect Tregs in patients with gastrointestinal cancer. METHODS: In this study, 45 gastric cancer patients, 50 colorectal cancer patients and 50 healthy controls were enrolled. Flow cytometry was used to detect CD4+CD25hiCD127low Tregs, CD4+CD25hi, and CD4+ cells in peripheral blood. Cytokine interleukin-10 (IL-10) and transforming growth factor-ß1 (TGF-ß1) in peripheral blood and in the supernatant of Tregs cultures were measured by enzyme linked immunosorbent assay. RESULTS: Compared with healthy controls, the levels of CD4+CD25hiCD127low Tregs and CD4+CD25hi cells increased significantly in patients with gastrointestinal cancer. Patients with gastrointestinal cancer also showed a significantly increased levels of IL-10 and TGF-ß1 in both peripheral blood and CD4+CD25hiCD127low Tregs culture medium. CONCLUSION: The present study firstly demonstrated that gastrointestinal patients have a compromised immune status where the CD4+CD25hiCD127low Tregs, as well as levels of IL-10 and TGF-ß1 are elevated. The data offered new information for understanding the immunological features of gastrointestinal patients, as well as provided new insights into approaches to develop new immunotherapies for patients with gastrointestinal cancer.

1α,25-dihydroxyvitamin D3 supplementation alleviates perfluorooctanesulfonate acid-induced reproductive injury in male mice: Modulation of Nrf2 mediated oxidative stress response.

Perfluorooctanesulfonate acid (PFOS) is a typical persistent organic pollutant that widely exists in the environment. To clarify the toxic effects and mechanisms of PFOS and to find effective intervention strategies have been attracted global attention. Here, we investigated the effects of PFOS on the male reproductive system and explored the potential protective role of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2 D3 ). Our results showed that 1α,25(OH)2 D3 intervention significantly improved PFOS-induced sperm quality decline and testicular damage. Moreover, 1α,25(OH)2 D3 aggrandized the total antioxidant capacity. Furthermore, after PFOS exposure, the transcription factor nuclear factor erythroid-related factor 2 (Nrf2) was adaptively increased together with its target genes, such as HO-1, NQO1, and SOD2. Meanwhile, 1α,25(OH)2 D3 ameliorated PFOS-induced augment of Nrf2 and target genes. These findings indicated that 1α,25(OH)2 D3 might attenuate PFOS-induced reproductive injury in male mice via Nrf2-mediated oxidative stress.

Effect of 1α,25(OH)2D3-Treated M1 and M2 Macrophages on Cell Proliferation and Migration Ability in Ovarian Cancer.

The biological active form of vitamin D3, 1α,25-dehydroxyvitamin D3 [1α,25(OH)2D3], exerts pleiotropic effects including bone mineralization, anti-tumor, as well as immunomodulator. This study aimed to explore the potential impact of 1α,25(OH)2D3 on tumor-associated macrophages (TAMs) infiltration in ovarian cancer. Firstly, human monocytic THP-1 cells were differentiated into macrophages (M0) in the presence of phorbol 12-myristate 13-acetate (PMA). In Vivo, 1α,25(OH)2D3 not only reversed the polarization of M2 macrophages, but also decreased the proliferation and migration abilities of ovarian cancer cells induced by M2 macrophages supernatant. Furthermore, 1α,25(OH)2D3 dramatically decreased the secretion of TGF-ß1 and MMP-9 in M2 macrophages. However, no significant effect was observed in 1α,25(OH)2D3 treated M1 macrophages. In Vivo, vitamin D3 had an inhibitive effect of 1α,25(OH)2D3-treated M2 macrophages on tumorigenesis. In addition, we conducted the association of TAMs with the poor prognosis of patients with ovarian cancer by meta-analysis, which suggested the higher proportion of M2 macrophages was related to the poorer prognosis in ovarian cancer. Collectively, these results identified distinct roles of 1α,25(OH)2D3 treated M1 and M2 macrophages on cell proliferation and migration abilities in ovarian cancer.

Quantitative Assessment of Water Quality Improvement by Reducing External Loadings at Lake Erhai, Southwest China.

To quantitatively evaluate the effects on water quality improvement caused by reducing external loadings entering Lake Erhai through inflow rivers, a one-dimensional hydrodynamic and ecological model (DYRESM-CAEDYM) was set up to simulate the water quality and water level variations. The calibrated and validated model was used to conduct six scenarios for evaluating the water quality responses to different amounts of external loading reduction at Lake Erhai. The results show (1) the total nitrogen (TN) concentration of Lake Erhai will be higher than 0.5 mg/L without any watershed pollution control during April-November 2025, which cannot meet Grade II standard of the China Surface Water Environmental Quality Standards (GB3838-2002). (2) External loading reductions can significantly reduce the concentrations of nutrients and Chla at Lake Erhai. The effects of water quality improvement will be proportional to the reduction rate of external loading reductions. (3) Internal release might be an important source of pollution It needs to be seriously considered as well as external loading for mitigating the eutrophication at Lake Erhai in the future.

Rice protein phosphatase 1 regulatory subunits OsINH2 and OsINH3 participate actively in growth and adaptive responses under abscisic acid.

Rice (Oryza sativa L.), a worldwide staple food crop, is affected by various environmental stressors that ultimately reduce yield. However, diversified physiological and molecular responses enable it to cope with adverse factors. It includes the integration of numerous signaling in which protein phosphatase 1 (PP1) plays a pivotal role. Research on PP1 has been mostly limited to the PP1 catalytic subunit in numerous cellular progressions. Therefore, we focused on the role of PP1 regulatory subunits (PP1r), OsINH2 and OsINH3, homologs of AtINH2 and AtINH3 in Arabidopsis, in rice growth and stress adaptations. Our observations revealed that these are ubiquitously expressed regulatory subunits that interacted and colocalized with their counter partners, type 1 protein phosphatase (OsTOPPs) but could not change their subcellular localization. The mutation in OsINH2 and OsINH3 reduced pollen viability, thereby affected rice fertility. They were involved in abscisic acid (ABA)-mediated inhibition of seed germination, perhaps by interacting with osmotic stress/ABA-activated protein kinases (OsSAPKs). Meanwhile, they positively participated in osmotic adjustment by proline biosynthesis, detoxifying reactive oxygen species (ROS) through peroxidases (POD), reducing malondialdehyde formation (MDA), and regulating stress-responsive genes. Moreover, their co-interaction proposed they might mediate cellular processes together or by co-regulation; however, the special behavior of two different PP1r is needed to explore. In a nutshell, this research enlightened the involvement of OsINH2 and OsINH3 in the reproductive growth of rice and adaptive strategies under stress. Hence, their genetic interaction with ABA components and deep mechanisms underlying osmotic regulation and ROS adjustment would explain their role in complex signaling. This research offers the basis for introducing stress-resistant crops.

Establishment and validation of an individualized nomogram for survival prediction of primary mediastinal germ cell tumors based on the SEER database.

Background: Primary mediastinal germ cell tumors (PMGCT) represent a rare but sometimes highly aggressive type of mediastinal tumors. The current prognostic models for PMGCT are insufficient. This study was undertaken to establish and validate an individualized nomogram for predicting the overall survival (OS) of patients with PMGCT. Methods: We conducted a retrospective analysis of patients with PMGCT diagnosed between 2000 and 2018 in the Surveillance, Epidemiology, and End Results (SEER) database in the United States. Clinical variables included surgery subtype, gender, treatment regimens, age, histology, tumor size, stage, chemotherapy, radiation, race, and survival-related information. The main outcome measure was survival duration. The Kaplan-Meier method along with the log-rank test were utilized to estimate the OS. Independent prognostic factors were identified by performing the univariate and multivariate Cox proportional hazards regression analyses, from which an individualized nomogram was constructed to predict 3-, 5-, and 10-year OS of patients with PMGCT. The concordance index (C-index) and calibration curve were used to verify the discrimination and accuracy of the nomogram. Results: A total of 845 patients with PMGCT were recruited from the SEER database and further randomly assigned to a training set (n=635) and a validation set (n=210) at a ratio of 7:3. The 3-, 5-, and 10-year OS for overall PMGCT was 70.0%, 67.1%, and 63.9%, respectively. Cox regression analysis indicated that age, tumor size, stage, chemotherapy, radiation, histology, and surgery type were as independent factors for OS in patients with PMGCT (P<0.05). An individualized nomogram for OS was constructed utilizing these variables, with the C-index of 0.714 [95% confidence interval (CI): 0.695 to 0.743] and 0.756 (95% CI: 0.735 to 0.787) in the training and validation groups. Moreover, good levels of agreement were observed according to the calibration curve between the predicted and actual 3-, 5-, and 10-year survival rates both in the training and validated cohorts, showing that the model could accurately predict patient prognosis. Conclusions: This study documented the first attempt at establishing and validating a novel nomogram for predicting the 3-, 5-, and 10-year OS probabilities of PMGCT. The prognostic nomogram was demonstrated to have good performance for predicting individualized OS of patients with PMGCT.

B7H6 Serves as a Negative Prognostic Marker and an Immune Modulator in Human Pancreatic Cancer.

Pancreatic cancer (PC), the third leading cause of cancer-related death in the U.S., is frequently found too late to be cured by traditional chemotherapy. Expression of B7 homolog 6 (B7H6), a member of the B7 family of immunoreceptors, has been found in PC and several other cancers. B7H6 is a ligand for cytotoxicity triggering receptor 3 (NKp30), which is expressed on NK cells. Here, we demonstrate that B7H6 can be detected in PC tissues but not normal organs. Its expression in patients associated significantly with tumor differentiation grade and lymphatic metastasis. The soluble form of B7H6 was detected in the PC patients' sera, and its concentration associated with tumor differentiation grade and tumor, node, metastasis (TNM) stages. Also, higher levels of B7H6 in PC patients' malignant tissues or serum correlated with shorter overall survival. In vitro, downregulation of B7H6 by CRISPR/Cas9 or siRNA technology had no significant impact on the viability or mobility of PC cells. Instead, knocking out B7H6 sensitized PC cells to NK-mediated cytotoxicity and cytokine production. These results indicate that B7H6 not only serves as a negative prognostic marker but also acts as an immune modulator in PC.

Effect of CMNa combined with radiotherapy on the tumor immune microenvironment of mouse cervical cancer cell transplantation tumor model.

In this study, we construct a subcutaneous tumor mice model of U14 cells, observe the tumor growth, and detect the expression of Foxp3 and VISTA in cervical cancer tissues and adjacent tissues during CMNa-enhancing radiotherapy.From the 15th day, compared with the control group, the tumor volume changes in each treatment group were significant (P < 0.01). CMNa combined with radiotherapy had an interactive effect and a positive effect in inhibiting tumor volume growth. There was no significant difference in the expression of Foxp3 and VISTA in mouse cervical cancer tissues and adjacent tissues in each group. The Foxp3 level in the RT group was the highest, and the CMNa group was the lowest. The VISTA level of the CMNa+RT group was the highest, the RT group is followed by, and the Control group is the lowest. The Foxp3 level of the CMNa group did not change much at each different point. The Foxp3 level in RT and CMNa+RT group gradually decreased after a transient increase, and the VISTA level in the CMNa+RT group increased more.Our results show that CMNa can enhance the efficacy of radiotherapy, and at the same time can reduce the compensatory increase in regulatory T cell Foxp3 levels caused by radiotherapy, and reduce the radiotherapy response. However, in the course of the treatment of the two, there may be a substantial increase in the level of VISTA, and the combined application of VISTA inhibitors may increase the anti-tumor response.

Prediction of Clinical Outcome in Endometrial Carcinoma Based on a 3-lncRNA Signature.

Endometrial carcinoma (EC) is one of the common gynecological cancers with increasing incidence and revived mortality recently. Given the heterogeneity of tumors and the complexity of lncRNAs, a panel of lncRNA biomarkers might be more precise and stable for prognosis. In the present study, we developed a new lncRNA model to predict the prognosis of patients with EC. EC-associated differentially expressed long noncoding RNAs (lncRNAs) were identified from The Cancer Genome Atlas (TCGA). Univariate COX regression and least absolute shrinkage and selection operator (LASSO) model were selected to find the 8-independent prognostic lncRNAs of EC patient. Furthermore, the risk score of the 3-lncRNA signature for overall survival (OS) was identified as CTD-2377D24.6 expression × 0.206 + RP4-616B8.5 × 0.341 + RP11-389G6.3 × 0.343 by multivariate Cox regression analysis. According to the median cutoff value of this prognostic signature, the EC samples were divided into two groups, high-risk set (3-lncRNAs at high levels) and low-risk set (3-lncRNAs at low levels), and the Kaplan-Meier survival curves demonstrated that the low-risk set had a higher survival rate than the high-risk set. In addition, the 3-lncRNA signature was closely linked with histological subtype (p = 0.0001), advanced clinical stage (p = 0.011), and clinical grade (p < 0.0001) in EC patients. Our clinical samples also confirmed that RP4-616B8.5, RP11-389G6.3, and CTD-2377D24.6 levels were increased in tumor tissues by qRT-PCR and in situ hybridization. Intriguingly, the p-value of combined 3-lncRNAs was lower than that of each lncRNA, indicating that the 3-lncRNA signature also showed higher performance in EC tissue than paracancerous. Functional analysis revealed that cortactin might be involved in the mechanism of 3-lncRNA signatures. These findings provide the first hint that a panel of lncRNAs may play a critical role in the initiation and metastasis of EC, indicating a new signature for early diagnosis and therapeutic strategy of uterine corpus endometrial carcinoma.

Erratum to "DAB2IP Downregulation Enhances the Proliferation and Metastasis of Human Gastric Cancer Cells by Derepressing the ERK1/2 Pathway".

[This corrects the article DOI: 10.1155/2018/2968252.].

A CARE-compliant case report: total pancreatectomy and total gastrectomy to treat pancreatic ductal adenocarcinoma.

RATIONALE: Total pancreatectomy (TP) is performed in cases of multifocal and large invasive tumors of the pancreas, and is associated with high rates of mortality and morbidity. Previously, the limitations and unsatisfactory effect of this surgery rendered it rarely performed; however, with improvements in surgical techniques and blood sugar management, TP is now more frequently performed. TP has a similar long-term survival rate as that for pancreatoduodenectomy (PD). However, the application of TP plus total gastrectomy (TG) for the treatment of invasive pancreatic ductal adenocarcinoma has not been reported previously. PATIENT CONCERNS: The patient was a 64-year-old man with epigastric discomfort. Physical examination showed a hard mass. Preoperative computed tomography and magnetic resonance imaging revealed a solid mass located in the pancreatic body and involving the portal vein and stomach. DIAGNOSIS: Pancreatic cancer. INTERVENTIONS: The patient was treated with TP combined with TG and portal vein reconstruction. OUTCOMES: The patient had a smooth post-operative recovery but, regretfully, developed metastases 2 months after discharge. LESSONS: Considering the poor outcome of the present case, the validity of the operation should be reevaluated. Although a single case does not elicit a convincing conclusion, the current case might serve as a warning against performing a similar surgery.

DAB2IP Downregulation Enhances the Proliferation and Metastasis of Human Gastric Cancer Cells by Derepressing the ERK1/2 Pathway.

DAB2IP (DOC2/DAB2 interactive protein) is downregulated in several cancer types, and its downregulation is involved in tumor cell proliferation, apoptosis, metastasis, and epithelial-mesenchymal transition (EMT). We aimed to investigate the potential role of DAB2IP in the development and progression of gastric cancer. DAB2IP levels were analyzed in human gastric cancer and adjacent normal tissues by Western blots and immunohistochemistry. Potential roles of DAB2IP in regulating gastric cancer cell growth and metastasis were examined by genetic manipulation in vitro. The molecular signaling was determined to understand the mechanisms of observed DAB2IP effects. DAB2IP level is lower in gastric cancer tissues as compared to paired normal tissues. Knockdown of DAB2IP enhanced gastric cancer cell growth and metastasis in vitro and promoted EMT progress at both protein and mRNA levels. Silencing DAB2IP activated extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, and the enhanced proliferation and migration ability induced by DAB2IP knockdown were reduced after incubation with U0126 in SGC7901 gastric cancer cells. Inhibition of DAB2IP enhances gastric cancer cell growth and metastasis through targeting the ERK1/2 signaling, indicating that it may serve as a potential target for treatment of gastric cancer.

Small interfering RNA-mediated knockdown of fatty acid synthase attenuates the proliferation and metastasis of human gastric cancer cells via the mTOR/Gli1 signaling pathway.

Fatty acid synthase (FASN), the main enzyme involved in de novo lipogenesis, is overexpressed in several types of tumor tissues. In addition, it is associated with tumor cell proliferation, metastasis, epithelial-mesenchymal transition (EMT) and a poor prognosis. However, the precise functions and internal mechanisms of FASN with regard to the proliferation, metastasis and EMT in gastric cancer (GC) cells remain elusive. The present study investigated FASN protein expression in 18 randomly selected pairs of GC tumors and matched normal tissues by western blot analysis. FASN-specific small interfering RNA (siRNA) was then transfected into SGC-7901 cells to examine the effect of FASN on proliferation and migration in vitro. Western blotting was used to detect the protein expression of FASN, EMT-related markers and key signaling molecules of the mechanistic target of rapamycin/zinc finger protein GLI1 (mTOR/Gli1) pathway. Reverse transcription-quantitative polymerase chain reaction was conducted to detect the mRNA expression of FASN and EMT-related markers. The FASN level was higher in the GC tissues compared with that in the surrounding normal tissues. Knockdown of FASN suppressed GC cell proliferation and metastasis in vitro. The silencing of FASN expression using siRNA reversed EMT at the protein and mRNA levels and decreased the expression of Gli1 via regulation of AMP-activated protein kinase/mTOR and protein kinase B/mTOR signaling in GC cells. Inhibition of FASN suppresses GC proliferation and metastasis through targeting of the mTOR/Gli1 signaling pathway, indicating that it may serve as a potential target for the treatment of GC.

FOXP3 and CEACAM6 expression and T cell infiltration in the occurrence and development of colon cancer.

The transcription factor forkhead box P3 (FOXP3) is involved in immune cell regulation, and carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is an adhesion molecule of the immunoglobulin superfamily. These two genes are associated with cancer progression. In the current study, colon tissue specimens from 78 cases of colon cancer (including 40 of stage I-II and 38 of stage III-IV), 30 cases of colonic adenoma and 12 healthy controls were collected from the First Affiliated Hospital of Soochow University between January 2010 and December 2011. The expression of cluster of differentiation (CD) 3, CD4, CD8, CD45RO, CEACAM6 and FOXP3 in colon tissues was examined by immunohistochemical analysis. In addition, a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay, based on SYBR Green I, was used to detect CD3, CD4, CD8, CD45RO, CEACAM6 and FOXP3 mRNA levels in the paraffin block specimens. CD3+, CD8+ and CD45RO+ T cell infiltrations in colonic adenoma were significantly higher than in normal colonic mucosa (P<0.001, P=0.001 and P<0.001, respectively). However, CD3+, CD8+ and CD45RO+ lymphocytes in stage III-IV colon cancer tissues were lower than in normal control tissues (P=0.015, P=0.002 and P=0.041, respectively); consistently, CD3+, CD4+, CD8+ and CD45RO+ lymphocytes in stage III-IV tissues were even more markedly lower compared with adenoma (P=0.001, P<0.001, P<0.001 and P<0.001, respectively). Similarly, CD3+, CD8+ and CD45RO+ T cell infiltration was lower in stage I-II cancer tissues compared with adenoma (P=0.001, P<0.001 and P<0.001). CD3+, CD4+, CD8+ and CD45RO+ T cell infiltrations were also significantly higher in stage I-II compared with stage III-IV cancer tissues (P<0.001, P=0.045, P<0.001 and P<0.001, respectively). CEACAM6 was found to gradually increase from normal colon tissue to adenoma and cancer tissue. FOXP3 was expressed more highly in stage I-II compared with normal tissues (P=0.014), and was even higher in stage III-IV (P<0.001). These results were verified using RT-qPCR, which yielded almost identical results. In summary, the current study demonstrates that FOXP3, CEACAM6 and T cell infiltration are significantly associated with the occurrence and progression of colon cancer, and that immune reactions vary between different stages of colon cancer development.