[A predictive model based on risk factors for early mortality in patients with newly diagnosed multiple myeloma].

Objective: To investigate risk factors for early mortality (EM) in patients with newly diagnosed multiple myeloma (NDMM) and to build an EM-predictive model. Methods: In a cohort of 275 patients with NDMM, risk factors for EM at 6, 12, and 24 months after diagnosis (EM6, EM12, and EM24, respectively) were determined to establish a model to predict EM. Results: The rates of EM6, EM12, and EM24 were 5.5% , 12.7% , and 30.2% , respectively. The most common cause for EM was disease progression/relapse, accounting for 60.0% , 77.1% , and 84.3% of EM6, EM12, and EM24, respectively. EM6 was associated with corrected serum calcium >2.75 mmol/L and platelet count <100×10(9)/L, whereas risk factors for EM12 included age >75 years, ISS Ⅲ, R-ISS Ⅲ, corrected serum calcium >2.75 mmol/L, serum creatinine >177 µmol/L, platelet count <100×10(9)/L, and bone marrow plasma cell ratio ≥ 60% . In addition to the risk factors for EM12, EM24 was also associated with male sex and 1q21 gain. By multivariate analysis, age >75 years, platelet count <100×10(9)/L, and 1q21 gain were independent risk factors for EM24 but there were no independent risk factors significantly associated with EM6 and EM12. Using a scoring system including these three risk factors, a Cox model for EM24 was generated to distinguish patients with low (score<3) and high (score ≥ 3) risk. The sensitivity and specificity of the model were 20.7% and 99.2% , respectively. Further, an internal validation performed in a cohort of 183 patients with NDMM revealed that the probability of EM24 in high-risk patients was 26 times higher than that in low-risk patients. Moreover, this model was also able to predict overall survival. The median overall survival of patients with scores of 0, 1, 2, 3, 4, and 5 were 59, 41, 22, 17.5, and 16 months, respectively. Conclusion: In the study cohort, the EM6, EM12, and EM24 rates were 5.5% , 12.7% , and 30.2% , respectively, and disease progression or relapse were main causes of EM. An EM24-predictive model built on three independent risk factors for EM24 (age>75 years, platelet count<100×10(9)/L, and 1q21 gain) might predict EM risk and overall survival.

CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer.

BACKGROUND: Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) metastasis and chemoresistance have not been fully characterized. METHODS: CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1. RESULTS: CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/ß-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients. CONCLUSIONS: CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC.

FBX8 is a metastasis suppressor downstream of miR-223 and targeting mTOR for degradation in colorectal carcinoma.

F-box proteins are critical components of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases and involved in the ubiquitin-dependent proteolytic pathway. Dysregulation of F-box protein-mediated proteolysis often leads to human malignancies. F-box only protein 8 (FBX8), a novel component of F-box proteins, is down-regulated in several tumors and closely correlates with tumor progression. However, little is known about its function, regulatory mechanisms and substrates in the progression of colorectal carcinoma (CRC). Combining microRNA (miRNA) assay, functional characterization, mechanistic studies with clinical validation, we identify FBX8 as a CRC metastasis suppressor downstream of miR-223, a metastasis promoting miRNA that is transcriptionally regulated by Myocyte enhancer factor (MEF2A). mTOR is a substrate of FBX8 for ubiquitin-mediated degradation and is required for FBX8 induced cell proliferation and invasion in CRC cells. FBX8 is down-regulated in human CRC tissues and correlates with MEF2A, miR-223 and mTOR expression levels. Notably, low FBX8 expression status in CRC tissues was a significant prognostic factor for poor overall survival of patients. These findings illustrate FBX8 as a metastasis suppressor that functions through mTOR signaling pathway and has significant prognostic power.

Iodine nutrition and thyroid diseases in Chengdu, China: an epidemiological study.

OBJECTIVE: To assess the iodine nutritional status and investigate the prevalence of thyroid diseases in a community population in Chengdu, China. METHODS: Eighty school-age children were randomly selected for measurements of urinary iodine concentration. A total of 1500 residents over the age of 18 who had lived in Chengdu for more than 5 years were selected by stratified cluster sampling. Serum thyroid hormone concentrations and thyroid autoantibodies were measured, and thyroid ultrasonography was performed. RESULTS: The median urine iodine concentration was 184 µg/l in school-age children. The prevalence of clinical hyperthyroidism, subclinical hyperthyroidism, clinical hypothyroidism and subclinical hypothyroidism was 0.97%, 1.95%, 0.90% and 5.55%, respectively. The prevalence of thyroid autoantibodies and thyroid nodules was 15.82% and 16.87%, respectively. The prevalence of clinical hyper- and hypothyroidism was greater in females than in males (P < 0.05). The prevalence of subclinical hyper- and hypothyroidism, thyroid nodules and thyroid autoantibodies increased significantly with age (P < 0.05). The rate of new abnormal TSH was 9.37%, and the average serum Thyroid Stimulating Hormone (TSH) concentrations increased with age. When TSH >0.71 mU/l, the prevalence of positive TPOAb and/or TgAb increased significantly with rising concentrations of TSH (P < 0.05); however, the prevalence of thyroid nodules did not increase with escalating concentrations of TSH (P = 0.09). CONCLUSION: Subclinical thyroid diseases, especially subclinical hypothyroidism and thyroid nodules, are common in an iodine sufficient area. Females and the elderly might benefit from routine screening for thyroid diseases, followed by appropriate detection and treatment.

Imaging of cardiac electrical excitation conduction.

We present a multiple time windows beamformer (MTWB) method of solving the inverse problem of magnetic field and non-invasively imaging the cardiac electrical excitation conduction using the magnetocardiac signals acquired by a 61-channel superconducting quantum interference device (SQUID). The MTWB constructs spatial filters for each location in source space, one for each component of the source moment based on the distributed source model, and estimates the cardiac equivalent current sources. The output of spatial filters is the source strength estimated in three-dimensional space and the weight matrix calculated with magnetocardiac signals in multiple time windows. A signal subspace projection technique is used to suppress noise. Then, the characteristics of cardiac electrical excitation conduction among two healthy subjects and two coronary vessel stenosis (CVS) patients are extracted from reconstructed current sources with maximum strength at each instant during QRS complex and ST-T segment, and a series of two-dimensional cardiac electrical excitation conduction maps (EECM) are obtained. It is demonstrated that two healthy subjects are of similar and the stronger electrical activities than those of two CVS patients. This technique can be used as an effective tool for the diagnosis of heart diseases.