Clinical Outcomes and Prognostic Factors in Stage III C Cervical Cancer Patients Treated with Radical Radiotherapy or Radiochemotherapy.

Objective: Since the update of the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging criteria, there have been few reports on the prognosis of stage III C cervical cancer. Moreover, some studies have drawn controversial conclusions, necessitating further verification. This study aims to evaluate the clinical outcomes and determine the prognostic factors for stage III C cervical cancer patients treated with radical radiotherapy or radiochemotherapy. Methods: The data of 117 stage III C cervical cancer patients (98 III C1 and 19 III C2) who underwent radical radiotherapy or radiochemotherapy were retrospectively analyzed. We evaluated 3-year overall survival (OS) and disease-free survival (DFS) using the Kaplan-Meier method. Prognostic factors were analyzed using the Log-rank test and Cox proportional hazard regression model. The risk of para-aortic lymph node metastasis (LNM) in all patients was assessed through Chi-squared test and logistic regression analysis. Results: For stage III C1 and III C2 patients, the 3-year OS rates were 77.6% and 63.2% (P = .042), and the 3-year DFS rates were 70.4% and 47.4% (P = .003), respectively. The pretreatment location of pelvic LNM, histological type, and FIGO stage was associated with OS (P = .033, .003, .042, respectively); the number of pelvic LNM and FIGO stage were associated with DFS (P = .015, .003, respectively). The histological type was an independent prognostic indicator for OS, and the numbers of pelvic LNM and FIGO stage were independent prognostic indicators for DFS. Furthermore, a pelvic LNM largest short-axis diameter ≥ 1.5 cm and the presence of common iliac LNM were identified as high-risk factors influencing para-aortic LNM in stage III C patients (P = .046, .006, respectively). Conclusions: The results of this study validated the 2018 FIGO staging criteria for stage III C cervical cancer patients undergoing concurrent chemoradiotherapy. These findings may enhance our understanding of the updated staging criteria and contribute to better management of patients in stage III C.

Biomarkers of lipid metabolism in gastric cancer: a case control study.

BACKGROUND: The aim of this study was to explore the correlation between biomarkers of lipid metabolism and gastric cancer. METHODS: 1120 gastric cancer patients and 1134 health examiners enrolled in this study. The clinic data and serum lipid level, including Total cholesterol (TC), Triglyceride (TG), Low-density lipoprotein cholesterol (LDL-C) and High-density lipoprotein cholesterol (HDL-C), were collected. RESULTS: Serum TG and LDL-C levels in patients with gastric cancer were higher than those in the control group. HDL-C levels were lower than the control group (P < 0.05). HDL-C and LDL-C were significantly correlated with the risk of gastric cancer. Concentrating on clinicopathological features, increased TG was more frequently in male patients with distal gastric cancer, N0 stage and early TNM stage. Increased TC was more frequently in early T, N and TNM stage. Decreased HDL-C was more common in distal location and low-undifferentiated gastric cancer. LDL-C elevation was more common in distal gastric cancer and early T stage. CONCLUSIONS: The serum lipid level of gastric cancer patients was higher than healthy controls. HDL-C and LDL-C abnormal correlated with gastric cancer risk. However, as the progresses of gastric cancer, poor patient intake, increased tumor consumption, and continuous declining in nutritional status, the levels of TC and TG gradually decreased in advanced gastric cancer.

LncRNA DGUOK-AS1 Promotes Cell Progression in Lung Squamous Cell Carcinoma by Regulation of miR-653-5p/SLC6A15 Axis.

Long noncoding RNA (lncRNA) plays a key role in regulating cancer development. LncRNA deoxyguanosine kinase antisense RNA 1 (DGUOK-AS1) has been reported as a promoter in tumor. The work was designed to further investigate the mechanism of action of DGUOK-AS1 in lung squamous cell carcinoma (LUSC). DGUOK-AS1 level in LUSC cells was measured using RT-qPCR. Counting Kit-8 assays and colony forming assays were performed to evaluate LUSC cell viability and proliferation. Transwell assays were performed to detect cell migration and invasion. Luciferase reporter and RNA pulldown assays were used to verify the binding capacity of DGUOK-AS1 and miR-653-5p. RNA immunoprecipitation assays were performed to verify the relationship of DGUOK-AS1, miR-653-5p, and SLC6A15. DGUOK-AS1 was highly expressed in LUSC cells. DGUOK-AS1 knockdown suppressed LUSC cell proliferation, migration, and invasion. SLC6A15 was demonstrated to be targeted by miR-653-5p, and DGUOK-AS1 interacted with miR-653-5p to modulate SLC6A15 level in LUSC cells. Overexpression of SLC6A15 reversed the suppressive effects of DGUOK-AS1 knockdown on LUSC cell processes. In conclusion, DGUOK-AS1 promotes malignant behaviors of LUSC cells by upregulating SLC6A15 level through interaction with miR-653-5p.

Optical Genome Mapping Reveals the Landscape of Structural Variations and Their Clinical Significance in HBOC-Related Breast Cancer.

BACKGROUND: Structural variations (SVs) are common genetic alterations in the human genome. However, the profile and clinical relevance of SVs in patients with hereditary breast and ovarian cancer (HBOC) syndrome (germline BRCA1/2 mutations) remains to be fully elucidated. METHODS: Twenty HBOC-related cancer samples (5 breast and 15 ovarian cancers) were studied by optical genome mapping (OGM) and next-generation sequencing (NGS) assays. RESULTS: The SV landscape in the 5 HBOC-related breast cancer samples was comprehensively investigated to determine the impact of intratumor SV heterogeneity on clinicopathological features and on the pattern of genetic alteration. SVs and copy number variations (CNVs) were common genetic events in HBOC-related breast cancer, with a median of 212 SVs and 107 CNVs per sample. The most frequently detected type of SV was insertion, followed by deletion. The 5 HBOC-related breast cancer samples were divided into SVhigh and SVlow groups according to the intratumor heterogeneity of SVs. SVhigh tumors were associated with higher Ki-67 expression, higher homologous recombination deficiency (HRD) scores, more mutated genes, and altered signaling pathways. Moreover, 60% of the HBOC-related breast cancer samples displayed chromothripsis, and 8 novel gene fusion events were identified by OGM and validated by transcriptome data. CONCLUSIONS: These findings suggest that OGM is a promising tool for the detection of SVs and CNVs in HBOC-related breast cancer. Furthermore, OGM can efficiently characterize chromothripsis events and novel gene fusions. SVhigh HBOC-related breast cancers were associated with unfavorable clinicopathological features. SVs may therefore have predictive and therapeutic significance for HBOC-related breast cancers in the clinic.

Heterogeneity and potential therapeutic insights for triple-negative breast cancer based on metabolic-associated molecular subtypes and genomic mutations.

Objective: Due to a lack of effective therapy, triple-negative breast cancer (TNBC) is extremely poor prognosis. Metabolic reprogramming is an important hallmark in tumorigenesis, cancer diagnosis, prognosis, and treatment. Categorizing metabolic patterns in TNBC is critical to combat heterogeneity and targeted therapeutics. Methods: 115 TNBC patients from TCGA were combined into a virtual cohort and verified by other verification sets, discovering differentially expressed genes (DEGs). To identify reliable metabolic features, we applied the same procedures to five independent datasets to verify the identified TNBC subtypes, which differed in terms of prognosis, metabolic characteristics, immune infiltration, clinical features, somatic mutation, and drug sensitivity. Results: In general, TNBC could be classified into two metabolically distinct subtypes. C1 had high immune checkpoint genes expression and immune and stromal scores, demonstrating sensitivity to the treatment of PD-1 inhibitors. On the other hand, C2 displayed a high variation in metabolism pathways involved in carbohydrate, lipid, and amino acid metabolism. More importantly, C2 was a lack of immune signatures, with late pathological stage, low immune infiltration and poor prognosis. Interestingly, C2 had a high mutation frequency in PIK3CA, KMT2D, and KMT2C and displayed significant activation of the PI3K and angiogenesis pathways. As a final output, we created a 100-gene classifier to reliably differentiate the TNBC subtypes and AKR1B10 was a potential biomarker for C2 subtypes. Conclusion: In conclusion, we identified two subtypes with distinct metabolic phenotypes, provided novel insights into TNBC heterogeneity, and provided a theoretical foundation for therapeutic strategies.

Development of an Active Surveillance or Surgery Model to Predict Lymph Node Metastasis in cN0 Papillary Thyroid Microcarcinoma.

Objective: Involvement of multiple lymph node (LN) metastasis in papillary thyroid microcarcinoma (PTMC) may indicate a progressive disease. To assist treatment decision, we conducted a clinical study to develop and validate a prediction model for the preoperative evaluation of LN metastasis involving more than five lymph nodes in patients with clinical N0 (cN0) PTMC. Material and Methods: Using data from 6,337 patients with cN0 PTMCs at Tianjin Medical University Cancer Institute and Hospital from 2013 to 2017, we identified and integrated risk factors for the prediction of multiple LN metastasis to build a nomogram. The predictive accuracy and discriminative ability of the nomogram were evaluated by the concordance index (C-index) and calibration curve. The model was validated using bootstrap resampling of the training cohort and an independent temporal validation cohort at the same institution. Results: In the training cohort (n = 3,209 patients), six independent risk factors were identified and included the prediction model (PTMC Active Surveillance or Surgery (ASOS) Model), including age, gender, multifocality, tumor size, calcification, and aspect ratio. The PTMC ASOS model was validated both internally and through the temporal validation cohort (n = 3,128 patients) from the same institute. The C-indexes of the prediction model in the training cohort were 0.768 (95% CI, 0.698-0.838), 0.768 and 0.771 in the internal validation and external validation cohorts, respectively. The area under the receiver operating characteristic curve (AUC) was 0.7068 and 0.6799. The calibration curve for probability of large-LN metastasis showed good agreement between prediction by nomogram and actual observation. DCA curves were used for comparison with another model, and IDI and NRI were also calculated. The cutoff value of our model was obtained by the ROC curve. Based on this model and cut point, a web-based dynamic nomogram was developed (https://tjmuch-thyroid.shinyapps.io/PTMCASOSM/). Conclusion: We established a novel nomogram that can help to distinguish preoperatively cN0 PTMC patients with or without metastasis of multiple lymph nodes. This clinical prediction model may be used in decision making for both active surveillance and surgery.

THE INFLUENCE OF LOW-DOSE OCCUPATIONAL RADIATION EXPOSURE ON PERIPHERAL BLOOD CELLS IN A COHORT OF CHINESE MEDICAL RADIATION WORKERS.

OBJECTIVES: The study aims to assess the change of peripheral blood cell numbers following protracted low-dose radiation exposure among medical radiation workers. METHODS: A cohort of 375 Chinese medical workers were followed for 5 years (2015-19) and recorded the changes in blood cells and cumulative doses. T-test, least significant difference-T test, variance analysis and correlation analysis were utilized in this study. RESULTS: Compared with the control group, the white blood cells, hemoglobin counts and the ratio of eosinophils in the study group showed a downward trend. The differences in blood cells between groups were mainly found in the number of red blood cells. In a short cumulative time, such as 1 or 3 years, a correlation between the cumulative dose and the quantity of blood cells was detected, but not at 5 years. CONCLUSIONS: There is no significant difference in the blood cell counts between different types of work, and the long-term cumulative dose has not been statistically correlated with the number of blood cells. So that the number of peripheral blood cells can no longer be used as a good indicator of radiation damage.

Perspectives on the role of breast cancer susceptibility gene in breast cancer.

PURPOSE: Breast cancer susceptibility gene 1/2 can repair damaged DNA through homologous recombination. Besides, the local immune microenvironment of breast cancer is closely linked to the prognosis of patients. But the relationship of breast cancer susceptibility gene 1/2 expression and local immunosuppressive microenvironment in breast cancer is not clear. The aim of this study was to discuss the correlation between them. METHODS: The fresh primary breast tumors and paired normal tissues of 156 cases of breast cancer patients as well as peripheral blood of 156 cases among them in Tianjin Medical University Cancer Institute and Hospital from January 2014 to October 2018 were collected. The association between breast cancer susceptibility gene 1/2 germline mutation and immune status of microenvironment in situ was analyzed. RESULTS: The results indicated that the germline mutation of breast cancer susceptibility gene 1/2 was inconsistent with the breast cancer susceptibility gene 1/2 protein expression, and the proportion of immune cells in patients with negative expression of breast cancer susceptibility gene 1/2 protein was higher than patients with positive expression of breast cancer susceptibility gene 1/2 protein (p < 0.05). And the expression of programmed cell death protein 1, cytotoxic T-Lymphocyte Antigen 4, programmed death ligand-1 of CD3+ T cells in patients with negative expression of breast cancer susceptibility gene 1/2 protein was higher than patients with positive expression of breast cancer susceptibility gene 1/2 protein (p < 0.05). The breast cancer susceptibility gene 1 protein expression was significantly correlated with family history of breast cancer patients (p = 0.006), local lymph node metastases (p = 0.001), and TNM staging (p ≤ 0.001). The breast cancer susceptibility gene 2 protein expression was significantly related to local lymph node metastases (p ≤ 0.001), III stage rate(p = 0.003) and molecular subtyping (p ≤ 0.001). Besides, the 5 years disease free survival was worse for G1 group and pathological III stage patients than other groups and other TNM stage patients. CONCLUSION: In short, the immune therapy may be a potential therapy method for breast cancer patients with negative expression of breast cancer susceptibility gene 1/2 protein.

Identification of Three Circulating MicroRNAs in Plasma as Clinical Biomarkers for Breast Cancer Detection.

The diagnostic value of microRNAs (miRNAs) for breast cancer (BC) is largely unknown. Here, our research aim was to explore new circulating miRNAs for BC diagnosis. First, we identified 14 common differentially expressed miRNAs in tissues by TCGA_BRCA and GSE97811 datasets and preliminarily validated them in serum by the GSE73002 dataset. Furthermore, we examined three plasma miRNAs in BC patients (n = 108) and healthy subjects (n = 103) by RT−PCR, namely, hsa-miR-100-5p, hsa-miR-191-5p and hsa-miR-342-3p. The levels of these three miRNAs in BC patients were higher than those in healthy controls (p < 0.05). The ROC curve analysis revealed that these three miRNAs had high diagnostic efficacy for BC and early-stage BC. The combination of hsa-miR-100-5p and hsa-miR-191-5p was the optimal combination for the diagnosis of BC and early-stage BC. Additionally, hsa-miR-100-5p was correlated with stage I−II, T1 stage, N0 stage and Luminal A subtype (p < 0.05). Hsa-miR-191-5p and hsa-miR-342-3p were irrelevant to TNM stage, T stage, N stage and molecular subtypes. Meanwhile, the biological function analysis indicated that these three miRNAs are mainly involved in the calcium signaling pathway, MAPK signaling pathway and microRNAs in cancer. In conclusion, these three miRNAs demonstrate a positive effect on detection and discovery in BC.

The mutation landscape of multiple cancer predisposition genes in Chinese familial/hereditary breast cancer families.

OBJECTIVE: Approximately 5%-10% of breast cancer (BC) patients display familial traits that are genetically inherited among the members of a family. The purpose of this study was to profile the germline mutations in 43 genes with different penetration rates and their correlations with phenotypic traits in Chinese familial BC families. METHODS: Ion Torrent S5™-based next generation sequencing was conducted on 116 subjects from 27 Chinese familial BC families. RESULTS: Eighty-one germline mutations in 27 BC predisposition genes were identified in 82.8% (96/116) of the cases. Among these, 80.8% of the mutated genes were related to DNA damage repair. Fourteen possible disease-causing variants were identified in 13 of 27 BC families. Only 25.9% (7/27) of the BC families exhibited hereditary deficiency in BRCA1/2 genes, while 22.2% of the BC families exhibited defects in non-BRCA genes. In all, 41.7% (40/96) of the mutation carriers had BRCA mutations, 88.5% (85/96) had non-BRCA mutations, and 30.2% (29/96) had both BRCA and non-BRCA mutations. The BC patients with BRCA mutations had a higher risk of axillary lymph node metastases than those without mutations (P < 0.05). However, the BC patients with non-BRCA mutations frequently had a higher occurrence of benign breast diseases than those without mutations (P < 0.05). CONCLUSIONS: In addition to BRCA1/2, genetic variants in non-BRCA DNA repair genes might play significant roles in the development of familial/hereditary BC. Therefore, profiling of multiple BC predisposition genes should be more valuable for screening potential pathogenic germline mutations in Chinese familial/hereditary BC.

High Risk Thyroid Nodule Discrimination and Management by Modified TI-RADS.

OBJECTIVE: Thyroid cancer is the most common primary malignant disorder of the thyroid. We aimed to illustrate the modified TI-RADS report system for differentiating malignant thyroid nodules from benign ones, and especially its role in the management of high risk nodules. METHODS: In this retrospective study, 5,162 healthy individuals who underwent thyroid ultrasound according to modified TI-RADS from January 2014 to December 2014 were enrolled and followed up during the whole 5 years, and the medical data were investigated and reviewed. RESULTS: The total detection rate of thyroid nodules was 39.40%. The total detection rate of thyroid cancer was 0.66%. Most thyroid cancers were single-shot, located at unilateral, at early clinical stages, without lymph node metastases, and with low recurrence risk. All patients had thyroid papillary carcinoma, except one thyroid medullary carcinoma. Based on modified TI-RADS classification, at the end of 5 years follow-up, more changes of thyroid nodules grade status were observed in grades 4a and above. The higher the grade status, the more malignant advances were occurred. The modified TI-RADS report system played an instructional role in adding medical treatment choice and decision for clinicians. CONCLUSION: The modified TI-RADS report system plays an important role in thyroid benign and malignant nodule identification and management.

Drug resistance gene expression and chemotherapy sensitivity detection in Chinese women with different molecular subtypes of breast cancer.

Objective: The aim of the study was to identify specific chemosensitivity drugs for various molecular subtypes of breast tumors in Chinese women, by detecting the expression of drug resistance genes and by using the drug sensitivity test on different molecular subtypes of breast cancers. Methods: The expression of drug resistance genes including Topo II, GST-π, P-gp, LRP, and CD133 were detected with immunohistochemistry in a tissue microarray. Drug sensitivity tests included those for paclitaxel, epirubicin, carboplatin, vinorelbine, and fluorouracil and were conducted on primary cancer tissue cells and cell lines, including the T47D, BT-474, and MDA-MB-231 cells and human breast cancer xenografts in nude mice. Results: The different drug resistant genes Topo II, GST-π, P-gp, and LRP were differentially expressed among different molecular subtypes of breast cancers (P < 0.05). Positive expression of CD133 was highest in basal-like breast cancer (P < 0.05). Kaplan-Meier survival analysis showed that positive expressions of Topo II and CD133 both correlated with shorter disease-free survival (DFS) (P < 0.05) and overall survival (P < 0.05), and positive expression of LRP correlated only with shorter DFS (P < 0.05). BT-474 showed chemosensitivity to paclitaxel and epirubicin, while MDA-MB-231 showed chemosensitivities to paclitaxel, epirubicin, carboplatin, and fluorouracil (T/C ≤ 50%). The basal-like and HER2+ breast cancer primary cells showed chemosensitivities to paclitaxel and epirubicin with significant differences compared with luminal breast cancer primary cells (P < 0.05). Conclusions: The differential expression of drug resistance genes and the differential chemosensitivities of drugs in different molecular subtype of breast cancers suggested that individual treatment should be given for each type of breast cancer.

Active surveillance as a management strategy for papillary thyroid microcarcinoma.

Active surveillance (AS) can be considered as a treatment strategy for low risk papillary thyroid microcarcinoma (PTMC), with the absence of clinically apparent lymph nodes, extrathyroidal extensions, and distant metastasis. After reviewing the reports on AS of low risk PTMCs worldwide, we introduced AS, and discussed the selection criteria for active surveillance candidates based on different guidelines and the follow-up schedules. Moreover, the requirement of cytological diagnosis, progression evaluation methods, necessity of thyrotropin suppression, and medical costs were issues that both clinicians and patients considered. The usefulness of AS for low risk PTMC patients depended on accurate and confidential evaluation of patient risk. Clinicians may adopt measures like dynamic monitoring, risk stratification, and making personal follow-up schedules to minimize these potential risks. By appropriately selecting PTMC patients, AS can be an effective alternative treatment to immediate surgery.

High Expression of Nuclear Transcription Factor-κB is Associated with Cisplatin Resistance and Prognosis for Ovarian Cancer.

BACKGROUND: Abnormal activation of the nuclear transcription factor-κB (NF-κB) signaling pathway plays a crucial role in the chemoresistance of tumor cells. This study aimed to explore the significance of NF-κB in the chemoresistance of ovarian cancer. MATERIALS: We performed immunohistochemical staining for evaluating the expression of NF-κB in cancer tissues. The MTT assay was performed for analyzing cell proliferation, Western blotting was performed to quantify NF-κB p65, and flow cytometry was used to determine the apoptosis rate. RESULTS: Nuclear NF-κB p65 over-expression was closely associated with ovarian cancer with advanced FIGO stage, residual disease ≥1 cm, low histologic grade, platinum resistance and refractory, chemotherapy resistance (P< 0.05). FIGO stage I-II and residual disease <1 cm were associated with complete response (CR) to chemotherapy, while FIGO stage I-II, residual disease <1cm and absence of lymph node (LN) metastasis were associated with platinum sensitivity. In multivariate logistic regression, residual disease ≥1 cm was a risk factor for response to chemotherapy, while the over-expression of nuclear NF-κB p65 was a risk factor for sensitivity to chemotherapy. In the ROC curves, nuclear NF-κB p65 expression had the discriminative ability for sensitivity to chemotherapy (AUC = 0.637, P = 0.021). Furthermore, nuclear NF-κB p65 expression was an independent prognostic factor. Western blotting showed that NF-κB p65 level in cisplatin-resistant cells (C13* and A2780cp) was significantly higher than that in cisplatin-sensitive cells (OV2008 and A2780s) (P < 0.05), and this increased expression could be suppressed by NF-κB inhibitor-PDTC treatment. The proliferation inhibitory rates of cisplatin in C13* and A2780cp cells increased after PDTC treatment in a concentration-dependent manner. PDTC treatment could also enhance cisplatin-induced apoptosis. CONCLUSION: NF-κB was associated with the clinicopathological features, chemoresistance, and prognosis of ovarian cancer. The NF-κB inhibitor PDTC can enhance cisplatin sensitivity of platinum-resistant C13* and A2780cp ovarian cancer cells.

ANGPTL4 overexpression is associated with progression and poor prognosis in breast cancer.

The aim of the present study was to analyze the expression levels of angiopoietin-like 4 (ANGPTL4) in breast cancer to investigate the association between ANGPTL4 and breast cancer. Immunohistochemistry was performed on formalin-fixed paraffin-embedded tissues, including 205 invasive ductal carcinoma (IDC) of no special type, 40 normal breast, 40 atypical ductal hyperplasia (ADH) and 40 ductal carcinomas in situ (DCIS) tissues. The non-parametric Kruskal-Wallis test was used to evaluate the differential expression of ANGPTL4 and clinicopathological parameters in breast cancer. Kaplan-Meier analysis and Cox regression analysis were used to evaluate the association between the expression levels of ANGPTL4 and the prognosis of breast cancer. The results revealed that ANGPTL4 expression was higher in IDC (63.4%; 130/205) compared with in normal breast tissues (17.5%; 7/40), ADH (30%; 12/40) and DCIS (37.5%; 15/40). The clinical significance of ANGPTL4 expression was analyzed in a total of 205 IDC tissues, and high expression levels of ANGPTL4 were positively associated with pathological stage (P<0.001), tumor size (P<0.001), histological grade (P<0.001), lymph node metastasis (P<0.001), distant metastasis (P<0.001) and local recurrence (P<0.001). Kaplan-Meier analysis revealed that patients with high ANGPTL4 expression had a shorter overall survival (OS; P<0.001) and disease-free survival (DFS; P<0.001) compared with patients with low ANGPTL4 expression. Multivariate Cox regression analysis revealed that ANGPTL4 was an independent prognostic factor for breast cancer OS (P=0.034) and DFS (P=0.011). The results of the present study demonstrated that ANGPLT4 was associated with malignant progression and poor prognosis of breast cancer, suggesting that ANGPLT4 may be a novel therapeutic target for breast cancer.

Dexmedetomidine pretreatment protects the heart against apoptosis in ischemia/reperfusion injury in diabetic rats by activating PI3K/Akt signaling in vivo and in vitro.

Dexmedetomidine (DEX) exerts cardioprotection against ischemia/reperfusion injury. However, the precise mechanisms underlying this cardioprotective effect in diabetic rats are still not fully understood. The aim of the present study was to investigate the cardioprotective mechanism of DEX pretreatment on myocardial ischemia/reperfusion (I/R) injury in diabetic rats. A total of 25 streptozotocin-induced diabetic rats were equally randomized into five groups: i) Sham, ii) DEX (100 µg/kg); iii) myocardial I/R; iv) myocardial I/R+DEX (10 µg/kg); and v) myocardial I/R+DEX (100 µg/kg) groups. Primary cardiomyocytes were cultured in DEX for 1 h, and then oxygen and glucose deprivation (OGD)/R for 36 h. These results showed that pretreatment with DEX significantly decreased the I/R-induced size of the myocardial infarction, structural damage, morphological changes and apoptosis in myocardial cells, as well as levels of creatinine kinase, malondialdehyde and cardiac troponin I, and increased the I/R-induced superoxide dismutase activity in vivo and in vitro. Furthermore, immunohistochemical staining and western blot analysis revealed that DEX pretreatment significantly increased the I/R-induced expression levels of B-cell lymphoma 2 (Bcl-2), phosphorylated phosphoinositide 3-kinase (pPI3K) and pAkt, and significantly decreased those of pBcl-2 associated agonist of cell death, Bcl-2-associated X protein and cleaved caspase 3 in vivo and in vitro. In addition, all of these cardioprotective effects of DEX were reversed by yohimbine and LY294002 pretreatment. These results suggested that DEX pretreatment may activate the PI3K/Akt signaling pathway in an α2 adrenoceptor-dependent manner. DEX pretreatment may exert cardioprotective effects against myocardial ischemia/reperfusion injury in diabetic rats through the I/R-induced inhibition of cell apoptosis by activating the PI3K/Akt signaling pathway.

Prognosis significance of indoleamine 2, 3-dioxygenase, programmed death ligand-1 and tumor-infiltrating immune cells in microenvironment of breast cancer.

INTRODUCTION: The immune microenvironment plays an increasingly important role in predicting the prognosis of multiple tumors and selecting patients for immunotherapy trials. We studied the expression of indoleamine 2, 3-dioxygenase (IDO) and programmed death ligand-1 (PD-L1), detected the proportion of tumor-infiltrating immune cells (TIIs), and further analyzed the association of these immunological characteristics with the clinicopathological parameters and prognosis of breast cancer patients. METHODS: Immunohistochemical staining for IDO, PD-L1, CD4, CD8, Foxp3, CD20, CD56 and CD68 expression in breast cancer tissues was carried out. IDO and PD-L1 expression were scored by extent in tumor cells. TIIs expressing CD4, CD8, Foxp3, CD20, CD56 or CD68 were evaluated by positive count. Clinicopathological characteristics and follow-up were recorded. RESULTS: The frequencies of IDO-high-expressing and PD-L1-expressing tissue were 33.77% and 24.68%, respectively. The co-expression of IDO and PD-L1 was identified in 16/77 (20.78%) of cases. IDO high expression, CD4+ T cells and CD56+ cells were most frequently observed in patients with tumor-draining lymph nodes(TDLNs) metastasis. Immune cells were more common in non-luminal breast cancer than in luminal breast cancer. In survival analysis, PFS were not associated with high levels of IDO and PD-L1, nor were TIIs. However, CD20 and CD68 were significant risk factors for prognostic after adjusting covariates by COX regression. IDOhighFoxp3highT patients had a tendency with shorter progression-free survival. CONCLUSIONS: Although we found a limited prognostic effect of TIIs on survival in breast cancer patients, IDO combined with TIIs can help to evaluate the prognosis of patients.

Chemoresistance was correlated with elevated expression and activity of indoleamine 2,3-dioxygenase in breast cancer.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) catalyses degradation of the essential amino acid tryptophan leading to the production of immunosuppressive kynurenine and tryptophan exhausting. IDO expression and activity contribute to aggressive tumor growth, inferior therapeutic gain and poor prognosis. The aim of this study was to explore the association between chemoresistance and IDO expression, activity in breast cancer METHODS: Immunohistochemistry was applied for evaluating IDO expression in biopsy tissues. Serum IDO activity was examined via High-performance liquid chromatography (HPLC). Western blots (WB), HPLC and Real-time PCR (RT-PCR) were used to analyze IDO protein, IDO enzyme activity and IDO gene expression in original and paclitaxel-resistant cells respectively. Logistic regression and survival analysis were applied to explore the association between chemoresistance and IDO expression, activity in breast cancer. RESULTS: IDO expression in tumor tissues was associated with serum IDO activity (P = 0.004). Both IDO expression in tumor and serum activity were associated with clinical tumor stage, node stage and estrogen receptor (ER) status (all P < 0.05); clinical response and pathologic complete response (pCR) to NAC were both related to IDO expression and activity prior NAC (all P < 0.05). Multivariate analysis showed IDO activity before NAC was the only independent factor affected pCR (P = 0.032). ROC curves showed that the IDO expression and activity had discriminative ability for predicting the clinical response and pCR. In the prognostic analysis, patients with high IDO expression had significantly impaired overall survival (5 year survival rate: 53.57% vs 80.00%) and progression-free survival (5 year survival rate: 46.43% vs 72.00%, P = 0.031 and P = 0.046). In vitro, significantly increased IDO protein, IDO mRNA expression and IDO enzyme activity in paclitaxel-resistant cells were demonstrated in comparing of sensitive cells. CONCLUSION: IDO expression and activity associated with advanced breast cancer, poor response to neoadjuvant chemotherapy and prognosis. IDO expression and activity were significantly increased in paclitaxel-resistant breast cancer cells.

CD4/CD8 + T cells, DC subsets, Foxp3, and IDO expression are predictive indictors of gastric cancer prognosis.

BACKGROUND: The tumor microenvironment represents an abnormal niche containing numerous factors, such as T cells, dendritic cells (DCs), regulatory T cells (Tregs), and indoleamine 2,3-dioxygenase (IDO), involved in maintaining immune homeostasis and tolerance. All these factors may influence the choice of therapy and the clinical outcomes. METHODS: Flow cytometry was performed to identify CD4+/CD8 + T cells and DCs, and immunohistochemistry was used to evaluate IDO and Forkhead Box P3 (Foxp3) expression; these experiments were performed in order to explore the clinical and prognostic significance of CD4/CD8 + T cells, DCs, Tregs, and IDO expression in gastric carcinoma. RESULTS: Smaller tumor size was correlated with higher expression levels of peripheral CD4 + T cells (P = .003) and CD8 + T cells (P = .002), and lower IDO expression (P = .044) in tumors. Well-differentiated gastric carcinomas displayed higher peripheral (P = .029) and tumor-infiltrating CD4 + T cell (P = .009) populations and a higher tumor-infiltrating DC1/DC2 ratio (P = .048). Gastric cancer in the early T stages exhibited higher populations of peripheral DC2s (P = .044) and a higher tumor-infiltrating DC1/DC2 ratio (P = .012). Gastric cancer at the N0 stage had lower tumor-infiltrating DC2s (P = .032) and a higher DC1/DC2 ratio (P = .037). IDO expression was positively correlated with tumor-infiltrating Foxp3 + Tregs (P < .001) as well as DC2s (P < .001), whereas it was negatively correlated with the tumor-infiltrating CD4/CD8 + T cell ratio (P = .023). Tumor-infiltrating Foxp3 + Treg was positively correlated with tumor-infiltrating DC2s (r2  = 0.772; P < .001). At T, N, and TNM stages, the expression levels of peripheral DC2s, tumor-infiltrating DC1/DC2 ratios, Foxp3 + Tregs, and IDO were significantly correlated with prognosis (P < .05). The T stage and peripheral DC2s were significant risk factors for overall survival. CONCLUSION: Immunocompetent cells and humoral immune factors, including DC2s, CD4+/CD8 + T cells, Foxp3 + Tregs, and IDO, interact with each other to compose a complex community of tumor immune microenvironment, ultimately affecting tumor progression and survival of gastric cancer.

LncRNA SNHG3 promotes clear cell renal cell carcinoma proliferation and migration by upregulating TOP2A.

LncRNA plays a vital role in many diseases, and abnormal expression of LncRNA has been reported in many types of tumors. In this study, we analyzed the available public TCGA and GEO databases, and found that the expression of SNHG3 was increased in clear cell renal cell carcinoma (ccRCC), which was positively correlated with many clinicopathological parameters, and the higher expression of SNHG3 predicted worse clinical prognosis. Functional experiments indicated that knockdown of SNHG3 could significantly inhibit the proliferation and metastasis of ccRCC in vitro and in vivo. Subsequently, through luciferase reporter assays, qPCR and rescue experiments, it was found that SNHG3 could bind to miR-139-5p, thereby up-regulating the expression of its target gene TOP2A, and play a role in promoting tumor progression in ccRCC. The correlation analysis showed that there was a significant positive correlation between the expression of SNHG3 and TOP2A, and both of them were significantly negative correlated with the expression of miR-139-5p. Our work suggested that the SNHG3/miR-139-5p/TOP2A axis plays an important role in the proliferation and metastasis of ccRCC, and was expected to be a new biomarker for diagnosis, prognosis and a target for treatment of ccRCC.