Exosomal microRNA-551b-3p from bone marrow-derived mesenchymal stromal cells inhibits breast cancer progression via regulating TRIM31/Akt signaling.

Mesenchymal stromal cells (MSCs) play an important role in the development of human cancer. Meanwhile, exosomes released by MSCs can mediate cell-cell communication by delivering microRNAs (miRNAs/miRs). Hence, this study aimed to explore the role of bone marrow mesenchymal stromal cell (BMSC)-derived exosomal miR-551b-3p in breast cancer. In this study, we found that upregulation of miR-551b-5p suppressed the proliferation and migration and induced the apoptosis of breast cancer cells via downregulating tripartite motif-containing protein 31 (TRIM31). In addition, miR-551b-5p could be transferred from BMSCs to breast cancer cells via exosomes; BMSC-derived exosomal miR-551b-3p suppressed the proliferation and migration and promoted the apoptosis and oxidative stress of MDA-MB-231 cells via inhibiting TRIM31. Furthermore, a xenograft mouse model was used to explore the role of BMSC-derived exosomal miR-551b-3p in vivo. We found that BMSC-derived exosomal miR-551b-3p inhibited tumor growth in a mouse xenograft model of breast cancer in vivo. Collectively, these findings indicated that BMSC-derived exosomal miR-551b-3p could suppress the development of breast cancer via downregulating TRIM31. Thus, miR-551b-3p could serve as a potential target for the treatment of breast cancer.

Multiplexed nanomaterial-assisted laser desorption/ionization for pan-cancer diagnosis and classification.

As cancer is increasingly considered a metabolic disorder, it is postulated that serum metabolite profiling can be a viable approach for detecting the presence of cancer. By multiplexing mass spectrometry fingerprints from two independent nanostructured matrixes through machine learning for highly sensitive detection and high throughput analysis, we report a laser desorption/ionization (LDI) mass spectrometry-based liquid biopsy for pan-cancer screening and classification. The Multiplexed Nanomaterial-Assisted LDI for Cancer Identification (MNALCI) is applied in 1,183 individuals that include 233 healthy controls and 950 patients with liver, lung, pancreatic, colorectal, gastric, thyroid cancers from two independent cohorts. MNALCI demonstrates 93% sensitivity at 91% specificity for distinguishing cancers from healthy controls in the internal validation cohort, and 84% sensitivity at 84% specificity in the external validation cohort, with up to eight metabolite biomarkers identified. In addition, across those six different cancers, the overall accuracy for identifying the tumor tissue of origin is 92% in the internal validation cohort and 85% in the external validation cohort. The excellent accuracy and minimum sample consumption make the high throughput assay a promising solution for non-invasive cancer diagnosis.

A Novel Prognostic Biomarker of Luminal Breast Cancer: High CD39 Expression Is Related to Poor Survival.

BACKGROUND: CD39 is one of the functional surface markers for T regulatory cells, the prognostic role and immune-related effects of CD39 in luminal breast cancer (BC) patients has not been evaluated yet. The aim of the current study was to explore the association between CD39 expression and clinic pathological characteristics and the prognosis in luminal BC patients. METHODS: Clinical information and RNA-sequencing (RNA-Seq) expression data were extracted from The Cancer Genome Atlas (TCGA). Patients were divided into a high or low CD39 expression group by the optimal cutoff value (4.18) identified from the receiver operating characteristic curve analysis. The relationships between CD39 expression and clinic pathological features were evaluated by the corresponding statistical tests. Survival analyses were applied to evaluate the overall survival between the high and low CD39 expression groups in luminal BC. Furthermore, Gene Expression Omnibus datasets were used for external data validation. Gene set enrichment analysis (GSEA) was also performed, and CIBERSORT was used to analyze the immune cell populations. RESULTS: Analysis of 439 cases of tumor data showed that CD39 was overexpressed in luminal BC. The multivariable analysis suggested that CD39 expression was an independent prognostic factor for luminal BC patients. GSEA suggested that CD39 might play an important role in luminal BC progression through immune regulation. Analysis of immune cell patterns revealed high CD39 expression correlated to a higher proportion of CD8+ T cells and M2 macrophages. CONCLUSION: This study demonstrates that CD39 expression correlates with the prognosis of luminal BC through TCGA database mining. Further studies are warranted further to elucidate this potential novel therapeutic strategy for BC.

Soil erosion and corn yield in a cultivated catchment of the Chinese Mollisol region.

Evaluation of soil redistribution rates and influence on crop yield in agricultural catchments is very important information, which can provide a scientific basis for arrangement of soil and water conservation measures and sustainable crop production. In recent decades, the soil erosion has greatly aggravated in the Mollisol region of Northeast China due to unreasonable land management, which in turn has reduced crop yield. The objectives of this study were to investigate the spatial distribution of soil redistribution and the relationship between crop yield and soil redistribute at a catchment of the Chinese Mollisol region. A total of 176 soil samples were collected based on a 200 m by 200 m grid and 4 yr of corn (Zea mays L.) yields were measured. The 137Cs trace technique and Zhang Xinbao's mass balance model indicated that the soil redistribution rates ranged from -7122.25 to 5471.70 t km-2 yr-1 and averaged -830.10 t km-2 yr-1. Soil erosion dominated in the research area. The corn yields for four years ranged from 43.24 to 136.19 kg km-2 and averaged 90.42 kg km-2. The spatial distribution of soil redistribution rates and corn yield showed a similar ribbon and plaque characteristics at the catchment. An equation between corn yield and soil redistribution rates was fitted and showed that there was a significant negative correlation between corn yield and soil erosion rates, while there was no relationship between the corn yield and soil deposition rates. Therefore, effective soil and water conservation measures are urgently needed to increase crop yield and realize sustainable land-use management.

Incidence, risk factors and prognostic characteristics of bone metastases and skeletal-related events (SREs) in breast cancer patients: A systematic review of the real world data.

PURPOSE: The aim was to systematically extrapolate the occurrence, risk factors, prognostic characteristics, management and outcome of bone metastases (BM) and skeletal related events (SREs) of breast cancer survivors in the real world clinical setting. METHODS: A systematic literature search of PubMed, Web of Science, EMBASE OvidSP and EBSCO Academic Search Complete was conducted. Published prospective and retrospective papers investigating BM and SREs in breast cancer patients in non-trial settings were identified and systematically reviewed. RESULTS: Twenty-four studies met the inclusion criteria. Incidences of BM based on new diagnosis, length of BM-free interval (BMFI) and number and sites of BM were detected by 17 of 24 studies. Seven studies included in the review were subjected to analyses of risk factors for BM. Developments of SREs regarding the occurrence ratio of total and specific SREs, SERs-free interval (SREFI) and the first-line therapy for SREs were observed in 16 of 24 studies. Out of 5 studies, we extracted uni- and multivariate analysis of risk factor for SREs and out of 16 studies - predictors for survival in breast cancer patients with BM. CONCLUSIONS: BM and SREs are common problems in non-trial breast cancer populations. Patient demographics, clinical stage, tumor pathological type, molecular receptors status are significantly risk factors for incidence of BM, SREs and the survival. The unique characteristics of BM and SREs in breast cancer patients should be taken into account in future randomized controlled trials, as to optimize individual treatment options and assure a maximally long good quality of life.

Appropriate Clinical Strategies for Breast Cancer Coexisting with Acute Myeloid Leukemia in the Genomic-Molecular Era: A Case Report.

BACKGROUND: The coexistence of breast cancer (BC) and acute myeloid leukemia (AML) has rarely been reported. Considering the fatality of AML, the management of this condition is based on treating the AML immediately while putting BC treatment on hold. CASE REPORT: Here, we report a synchronous occurrence of BC and AML. Prognostic factors for both BC and AML were determined by genomic and molecular evaluation. The evaluation for AML showed a relatively good prognosis, and we simultaneously conducted treatment for AML and BC. The patient has survived for more than 3 years, which makes this the case with the longest survival reported. CONCLUSION: In patients with BC and AML, it is essential to determine the prognosis through a genomic and molecular evaluation. For a certain group of patients whose prognosis of AML is good, simultaneous or initial treatment of BC before treatment of AML may be appropriate.

Breast-specific gamma imaging with Tc-99m-sestamibi in the diagnosis of breast cancer and its semiquantitative index correlation with tumor biologic markers, subtypes, and clinicopathologic characteristics.

OBJECTIVES: To determine the sensitivity of breast-specific gamma imaging (BSGI) in diagnosing breast cancer and assess the potential correlation between the semiquantitative index of BSGI and biologic markers, molecular subtypes, and clinicopathologic characteristics of breast cancer. MATERIALS AND METHODS: The sensitivity of BSGI for breast cancer was retrospectively assessed in 102 female breast cancer patients who underwent BSGI before surgery and was compared with that of ultrasonography and mammography. BSGI was visually graded on the basis of the Society of Nuclear Medicine and Molecular Imaging guideline. Tracer uptake in the cancer as the lesion to nonlesion ratio (L/N) was calculated semiquantitatively and was subsequently correlated to tumor biologic markers, molecular subtypes, and clinicopathologic characteristics. RESULTS: The sensitivity of BSGI for breast cancer by visual analysis was 94.1% (96/102) in our cohort, which was 100% (47/47) in the subgroup of patients with a tumor size more than 2.0 cm and 89.1% (49/55) in the subgroup of patients with a size less than or equal to 2.0 cm. The sensitivity of BSGI was significantly higher than that of ultrasonography of 84.2% (85/101) (P=0.022) and mammography of 84.5% (60/71) (P=0.037). There was no significant correlation between the L/N and expressions of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and antigen Ki-67, and the subtypes or histologic grade of the cancer (P>0.05). However, the value of L/N was associated with infiltration degree (P=0.005), axillary lymph node status (P=0.029), and tumor size (P=0.002). Multivariate analysis further indicated that the value of L/N was correlated with infiltration degree (P=0.016) and tumor size (P=0.002). CONCLUSION: BSGI has a high sensitivity for detecting primary breast cancer. The value of L/N on BSGI was independently related to infiltration degree and tumor size of breast cancer, but not to expression of tumor receptor markers and histologic grade.

The Effectiveness of Radioactive Iodine Remnant Ablation for Papillary Thyroid Microcarcinoma: A Systematic Review and Meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to evaluate the effectiveness of radioactive iodine (RAI) remnant ablation for thyroid cancer-related outcomes of patients with papillary thyroid microcarcinoma (PTMC). METHODS: A systematic literature search of PubMed, EMBASE OvidSP, and EBSCO was conducted. Studies were selected that provided multivariable analysis of the effectiveness of RAI ablation or provided specific data of a 10 years history of thyroid cancer-related outcomes in patients that presented with PTMC. RESULTS: Nineteen studies met the inclusion criteria. A multivariable analysis of the effectiveness of RAI ablation for any recurrence or thyroid cancer-related mortality in patients with PTMC was performed in several studies, among which only one study reported a positive result. Furthermore, for PTMC patients treated by total or near-total thyroidectomy (TT/NT), with or without RAI ablative therapy, the meta-analysis suggested that RAI ablation did not decrease the 10 years history of any tumor recurrence (relative risk [RR] 0.96; 95% confidence interval [CI] 0.63-1.48; P = 0.87), locoregional recurrence (RR 1.15; 95% CI 0.75-1.76; P = 0.51), distant metastases (RR 0.32; 95% CI 0.08-1.32; P = 0.11) or thyroid cancer-related mortality (RR 0.76; 95% CI 0.22-2.63; P = 0.66). CONCLUSIONS: With regard to multivariable analyses, there was almost no positive treatment effect of RAI ablation noted for patients with PTMC. For PTMC patients already treated by TT/NT, incremental RAI ablation may not be beneficial at decreasing the 10 years recurrence of PTMC or incidence of thyroid cancer-related mortality.

Association between cytochrome P450 2C9 gene polymorphisms and colorectal cancer susceptibility: evidence from 16 case-control studies.

Previous epidemiological studies have evaluated the association between common variations of cytochrome P450 (CYP)2C9 (430C>T and 1075A>C) and the risk of colorectal cancer (CRC) with conflicting results. To derive a more precise estimation of the relationship between these CYP2C9 polymorphisms and CRC, a meta-analysis was performed. PubMed, Embase, CNKI, and Web of Science databases were searched. A total of 16 studies including 9,463 cases and 11,416 controls were identified. Potential sources of heterogeneity including ethnicity, sample size of study, genotyping method, diagnostic criteria, and outcome were systematically assessed. Overall, the summary odds ratio of 430T variant for CRC was 0.92 (95% confidence interval (CI) 0.86-0.98; P = 0.012) and 1.39 (95% CI 1.07-1.81; P = 0.013) for colorectal adenomas (CRAs). As for CYP2C9 1075A>C polymorphism, no significant results were observed in overall and subgroup analysis. There was no evidence of publication bias. In conclusion, there is evidence to indicate a significant association between CYP2C9 430C>T polymorphism and CRC/CRA risk.

Association between 1p11-rs11249433 polymorphism and breast cancer susceptibility: evidence from 15 case-control studies.

Genome-wide association studies have identified SNP rs11249433 at chromosome 1p11 as a new breast cancer (BC) susceptibility locus in populations of European descent. Since then, the relationship between 1p11- rs11249433 and breast cancer has been reported in various ethnic groups; however, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 15 studies involving a total of 90,154 cases and 137,238 controls for 1p11-rs11249433 polymorphism to evaluate its effect on genetic susceptibility for breast cancer. An overall random effects odds ratio of 1.09 (95% CI: 1.06-1.12, P<10(-5)) was found for rs11249433-G variant. Significant results were also observed for heterozygous (OR=1.09, 95% CI: 1.05-1.12, P<10(-5)) and homozygote (OR=1.14, 95% CI: 1.08-1.21, P<10(-5)). There was strong evidence of heterogeneity, which largely disappeared after stratification by ethnicity. After stratified by ethnicity, significant associations were found among Caucasians. However, no significant associations were detected among East Asian and African populations. In addition, we found that rs11249433 polymorphism on 1p11 confer risk, exclusively for ER-positive tumors with per-allele OR of 1.13 (95% CI: 1.08-1.18; P <10(-5)) compared to ER-negative tumors of 1.01 (95% CI: 0.98-1.04; P=0.49). Similar results were also observed when stratified by PR status. Our findings demonstrated that rs11249433-G allele is a risk-conferring factor for the development of breast cancer, especially in Caucasians.

Genetically engineered K cells provide sufficient insulin to correct hyperglycemia in a nude murine model.

A gene therapy-based treatment of type 1 diabetes mellitus requires the development of a surrogate beta cell that can synthesize and secrete functionally active insulin in response to physiologically relevant changes in ambient glucose levels. In this study, the murine enteroendocrine cell line STC-1 was genetically modified by stable transfection. Two clone cells were selected (STC-1-2 and STC-1-14) that secreted the highest levels of insulin among the 22 clones expressing insulin from 0 to 157.2 microIU/ml/10(6) cells/d. After glucose concentration in the culture medium was increased from 1 mM to 10 mM, secreted insulin rose from 40.3+/-0.8 to 56.3+/-3.2 microIU/ml (STC-1-2), and from 10.8+/-0.8 to 23.6+/-2.3 microIU/ml (STC-1-14). After STC-1-14 cells were implanted into diabetic nude mice, their blood glucose levels were reduced to normal. Body weight loss was also ameliorated. Our data suggested that genetically engineered K cells secrete active insulin in a glucose-regulated manner, and in vivo study showed that hyperglycemia could be reversed by implantation of the cells, suggesting that the use of genetically engineered K cells to express human insulin might provide a glucose-regulated approach to treat diabetic hyperglycemia.

Caspase-3 expression in human gastric carcinoma and its clinical significance.

OBJECTIVES: Caspase-3 is one of the most important molecules in the apoptosis cascade, and the relationship between caspase-3 expression and prognosis has been reported in many types of malignancies. However, the involvement of caspase-3 in human gastric carcinoma is not fully understood. We evaluated caspase-3 expression in human gastric carcinoma to clarify the clinicopathological importance and investigated the apoptosis avoidance mechanism by an immunohistological method. METHODS: Specimens from 151 patients who underwent gastrectomy at the Department of Surgery and Surgical Basic Science of Kyoto University Hospital were investigated. Caspase-3 expression in cancer cells was evaluated by comparing its expression in the germinal center of the lymphoid follicle, and was quantified as the caspase-3 expression index (C3EI). C3EI was compared with the expression of Bcl-2 and the TdT-mediated dUTP biotin nick-end labeling (TUNEL) in 80 randomly selected cases. Actual activation of caspase-3 was determined by immunohistochemistry using monoclonal antibody that recognizes only activated caspase-3. RESULTS: C3EI correlated significantly with lymph node metastasis (negative 105.5-78.7, positive 153.8 +/- 66.1 p = 0.001) and the lower C3EI group had a better prognosis than the higher group (log-rank test, p = 0.0001). Cox multivariate analysis showed that age, operation curability, tumor invasion and C3EI were significant independent determinants of overall survival. Bcl-2 and TUNEL staining had no significant correlations with C3EI. Immunohistochemistry of activated caspase-3 revealed that most caspase-3 in gastric cancer cells was not activated, in accordance with TUNEL assay. CONCLUSIONS: Our results show that C3EI is a novel, independent prognostic factor in gastric cancer patients and cancer cells may avoid apoptosis by inhibiting caspase-3 activation.

Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance.

BACKGROUND/AIMS: We analyzed the expressions of hexokinase II (HK II), a key enzyme in glycolysis, and VEGF in hepatocellular carcinoma (HCC) and metastatic liver cancer in relation to tumor vascularity, and the participation of hypoxia-inducible factor-1 (HIF-1) was studied. METHODS: A real-time quantitative reverse transcription-polymerase chain reaction was performed to examine the HK II and VEGF mRNA expression. Expression of HIF-1 alpha and HK II protein, and microvessel density (MVD) were examined immunohistochemically. RESULTS: MVD was significantly higher in HCCs than in metastatic liver cancers, and VEGF mRNA expression was positively correlated only with MVD of HCCs. HK II mRNA expression was significantly higher in metastatic liver cancers, however, some cases of HCC pretreated with transcatheter arterial embolization (TAE) showed marked HK II mRNA expression. Both HIF-1 alpha and HK II protein expressions were co-localized in the cancer cells near necrosis, and the intensity of HIF-1 alpha protein expression was significantly correlated with HK II mRNA expression in both tumors. CONCLUSIONS: These results suggest that, in metastatic liver cancers, glycolysis induced by HIF-1 is the predominant energy source under the hypoxic environment and, at least in some TAE-pretreated HCC cases, cancer cells obtain energy for growth by switching the metabolic profile to glycolysis through HIF-1.

Interleukin-12-gene transduction makes DCs from tumor-bearing mice an effective inducer of tumor-specific immunity in a peritoneal dissemination model.

Dendritic cells (DCs) from cancer patients, as well as tumor-infiltrating DCs, are reported to have suppressed immunostimulatory capacity. One of the major problems in the clinical use of DCs for treating tumors is that the DCs must be autologous ones obtained from patients. Compared with normal DCs (nDCs), flow-cytometric analysis and allogeneic mixed lymphocyte reaction (MLR) have revealed lower expression of the costimulatory molecules and suppressed T-cell-stimulatory activity in DCs derived from tumor-bearing mice (tDCs) despite of culture. We reported previously that the interleukin-12 (IL-12)-gene-transduced nDCs inhibited tumor growth due to induced tumor-specific Th1 and cytotoxic T cells (CTLs) in a murine established subcutaneous tumor model. In the present study, we examined whether tDCs could induce immune responses against tumors after IL-12-gene transduction in an established peritoneal dissemination model. The intraperitoneal injection of IL-12-gene-transduced tDCs resulted in prolonged survival of some treated mice (log-rank test; P=0.001) and tumor-specific Th1 and CTL activity. The injection of IL-12-gene-transduced nDCs prolonged the survival of all treated mice (P<0.0001) and elicited tumor-specific immunity, which were better than those of IL-12-gene-transduced tDCs. Taken together, DC modification of IL-12-gene transduction is an effective and promising approach for cancer therapy even when immunosuppressive tDCs are employed.