Analysis of Facts and Dilemmas of Globalization Activities

This paper critically analyzes the key elements (world trends, national identity, human resources, market) of the effects of globalization on the market, as well as the role of our country in the entire process, listing practical examples. Through comparison and analysis of the available literature and experience, it was concluded that there is a dual impact of globalization in the economic sphere and the need for including management into world trends is increasing. The turbulent environment demands increasingly rapid adaptation of outdated management methods towards more progressive and modern methods, for that which was new yesterday may already be old today.globalization, economy, management, market

Ultraconserved Enhancers Roles in Cancer

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Effects of dietary protein and phosphorus restriction on the progression of early renal failure

Effects of dietary protein and phosphorus restriction on the progression of early renal failure. Three groups of patients with chronic renal failure were studied. Group 1 comprised 25 patients with a mean serum creatinine of 2.18mg/dl and a mean arterial pressure of 117mm Hg. Group 2 had 20 patients with a mean serum creatinine of 4.24mg/dl and a mean arterial pressure of 119mm Hg. All these patients were kept for 18 to 76 months on a diet containing about 40 kcal/kg, 0.6 g/kg of protein, 700mg of phosphorus, and 1,000 to 1,500mg of calcium (orally supplemented). Group 3 comprised 30 patients with a mean serum creatinine of 2.28mg/dl and a mean arterial pressure of 116mm Hg. They had followed no specific dietary regimen for 3 to 72 months, and their dietary calorie, protein, phosphorus, and calcium intakes averaged 35 kcal/kg, 70 g, 900mg, and 800mg, respectively. The plots of reciprocal creatinine against time gave slopes of -0.0008 and -0.0010 in patients in groups 1 and 2, and a slope of -0.020 in group 3 patients. The slopes of both groups 1 and 2 were statistically different (analysis of variance and “F” test, P < 0.01) from that of group 3. No evidence of progressive protein and phosphorus depletion was observed in groups 1 and 2 patients. We conclude that a moderate dietary restriction of protein and phosphorus is an acceptable and effective regimen for delaying progression of functional deterioration in early renal failure.Effet de la restriction protéique et phosphorée alimentaire sur la progression de l'insuffisance rénale débutante. Trois groupes de malades ayant une insuffisance rénale chronique ont été étudiés. Le groupe 1 comprenait 25 malades ayant une créatinine sérique moyenne de 2,18mg/dl et une pression artérielle moyenne de 117mm Hg. Le groupe 2 comportait 20 malades ayant une créatinine sérique moyenne de 4,24mg/dl et une pression artérielle moyenne de 119mm Hg. Tous ces malades ont été soumis pendant 18 à 76 mois à un régime contenant environ 40 kcal/kg, 0,6kg de protéines, 700mg de phosphore, et 1000 à 1500mg de calcium (par supplémentation orale). Le groupe 3 comprenait 30 malades ayant une créatinine sérique moyenne de 2,28mg/dl et une pression artérielle moyenne de 116mm Hg. Ils n'avaient pas suivi de régime alimentaire spécifique pendant 3 à 72 mois, et leurs apports alimentaires caloriques, protéiques, phosphorés et calciques étaient en moyenne de 35 kcal/kg, 70 g, 900mg, et 800mg, respectivement. Les courbes de créatinine en fonction du temps ont donné des pentes de -0,0008 et de -0,0010 chez les malades des groupes 1 et 2, et une pente de -0,020 chez ceux de groupe 3. Des pentes des groupes 1 et 2 différaient statistiquement (analyse de variance et test de “F”, P < 0,01) de ceux du groupe 3. Il n'a pas été observé de preuve de déplétion progressive en protéines et en phosphore chez les malades des groupes 1 et 2. Nous concluons qu'une restriction alimentaire modérée en protéines et en phosphore est un régime acceptable et efficace pour retarder la progression de la détérioration fonctionnelle au cours de l'insuffisance rénale précoce

MiR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2

Myelofibros is (MF) is a myeloproliferative neoplasm characterized by cytopenia and extramedullary hematopoiesis, resulting in splenomegaly. Multiple pathological mechanisms (e.g., circulating cytokines and genetic alterations, such as JAK(V617F) mutation) have been implicated in the etiology of MF, but the molecular mechanism causing resistance to JAK(V617F) inhibitor therapy remains unknown. Among MF patients who were treated with the JAK inhibitor ruxolitinib, we compared noncoding RNA profiles of ruxolitinib therapy responders versus nonresponders and found miR-S43 was significantly upregulated in non responders. We validated these findings by reverse transcription-quantitative PCR. in this same cohort, in 2 additional independent MF patient cohorts from the United States and Romania, and in a JAK2(V617F) mouse model of MF. Both in vitro and in vivo models were used to determine the underlying molecular mechanism of miR-543 in MF. Here, we demonstrate that miR-543 targets the dioxygenases ten-eleven translocation 1 (TET1) and 2 (TET2) in patients and in vitro, causing increased levels of global 5-methylcytosine, while decreasing the acetylation of histone 3, STAT3, and tumor protein p53. Mechanistically, we found that activation of STAT3 by JAKs epigenetically controls miR-543 expression via binding the promoter region of miR-543. Furthermore, miR-543 upregulation promotes the expression of genes related to drug metabolism, including CYP3A4, which is involved in ruxolitinib metabolism. Our findings suggest miR-543 as a potentially novel biomarker for the prognosis of MF patients with a high risk of treatment resistance and as a potentially new target for the development of new treatment options

17β-estradiol promotes extracellular vesicle release and selective miRNA loading in ERα-positive breast cancer

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor–positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7’s miRNAs into EVs. In multiple patient cohorts, we observed increased levels of let-7a-5p and let-7d-5p in EVs derived from the blood of premenopausal ER+ BC patients, and elevated EV levels in patients with high BMI, both conditions associated with higher levels of 17β-estradiol. In brief, we identified a unique estrogen-driven mechanism by which ER+ BC cells eliminate tumor suppressor miRNAs in EVs, with effects on modulating tumor-associated macrophages in the microenvironment

N-BLR, a primate-specific non-coding transcript leads to colorectal cancer invasion and migration

Background: non-coding RNAs have been drawing increasing attention in recent years as functional data suggest that they play important roles in key cellular processes. N-BLR is a primate-specific long non-coding RNA that modulates the epithelial-to-mesenchymal transition, facilitates cell migration, and increases colorectal cancer invasion. Results: we performed multivariate analyses of data from two independent cohorts of colorectal cancer patients and show that the abundance of N-BLR is associated with tumor stage, invasion potential, and overall patient survival. Through in vitro and in vivo experiments we found that N-BLR facilitates migration primarily via crosstalk with E-cadherin and ZEB1. We showed that this crosstalk is mediated by a pyknon, a short ~20 nucleotide-long DNA motif contained in the N-BLR transcript and is targeted by members of the miR-200 family. In light of these findings, we used a microarray to investigate the expression patterns of other pyknon-containing genomic loci. We found multiple such loci that are differentially transcribed between healthy and diseased tissues in colorectal cancer and chronic lymphocytic leukemia. Moreover, we identified several new loci whose expression correlates with the colorectal cancer patients' overall survival. Conclusions: the primate-specific N-BLR is a novel molecular contributor to the complex mechanisms that underlie metastasis in colorectal cancer and a potential novel biomarker for this disease. The presence of a functional pyknon within N-BLR and the related finding that many more pyknon-containing genomic loci in the human genome exhibit tissue-specific and disease-specific expression suggests the possibility of an alternative class of biomarkers and therapeutic targets that are primate-specific

Role of T198 Modification in the Regulation of p27Kip1 Protein Stability and Function

The tumor suppressor gene p27Kip1 plays a fundamental role in human cancer progression. Its expression and/or functions are altered in almost all the different tumor histotype analyzed so far. Recently, it has been demonstrated that the tumor suppression function of p27 resides not only in the ability to inhibit Cyclins/CDKs complexes through its N-terminal domain but also in the capacity to modulate cell motility through its C-terminal portion. Particular interest has been raised by the last amino-acid, (Threonine 198) in the regulation of both protein stability and cell motility

The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling

BACKGROUND &amp; AIMS: Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic.METHODS: We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, gamma-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2'-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients.RESULTS: High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients.CONCLUSIONS: We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors