First report of inherited thyroxine-binding globulin deficiency in Iran caused by a known de novo mutation in SERPINA7

Background Thyroxine-binding globulin (TBG) is the main transporter of thyroid hormones in human serum, encoded by the gene TBG (SERPINA7), located in long arm of X-chromosome (Xq21-q22). Deficiency of SERPINA7 (serum protease inhibitor, clade A alpha-1 antiproteinase, antitrypsin, member 7) leads to inherited TBG deficiency. Several mutations have been reported in the coding and noncoding regions of SERPINA7 in association with TGB deficiency. Methods Automated chemiluminescence immunoassays were used to determine TSH, free and total T4 and T3 (fT4, TT4, TT3) and TBG. Direct DNA sequencing identified the mutation in SERPINA7. Results We present a 3 and 4/12 year old boy, born premature, who was mismanaged as hypothyroidism before referral to our center, and was diagnosed with TBG deficiency at our center with a hemizygous substitution in exon 1, position c.347T > A, leading to replacement of isoleucine for arginine in position 96 (considering the first 20 amino acid signal peptide). Conclusion This known mutation, reported as the first SERPINA7 mutation in Iran, emphasizes the point that endocrinologists should pay more attention to inherited TBG to prevent unnecessary treatment

Effect of β-glucan on serum levels of IL-12, hs-CRP, and clinical outcomes in multiple-trauma patients: A prospective randomized study �oklu travma hastalarda β �glukanın serum IL-12, hs-CRP de�erleri ve klinik sonuçları üzerine etkisi: Ileriye yönelik randomize çalı�ma

BACKGROUND: Trauma is associated with a profound immunological dysfunction. This predisposes patients to infections and adverse outcomes. β-glucan has been implicated in the initiation of anti-microbial immune response. The present study aimed to evaluate the effects of an enteral diet containing β-glucan on serum levels of IL-12 and highly-sensitive C-reactive protein (hs-CRP), occurrence of infection, and clinical outcomes in critically ill multiple-trauma patients. METHODS: Forty multiple-trauma patients requiring enteral nutrition for at least 10 days were randomly assigned to the intervention group (n=20) or the placebo group (n=20). The intervention group received a high-protein enteral diet providing 3 g β-glucan, and the control group received a similar diet, except for 3 g of maltodextrin as a placebo. Serum levels of IL-12 and hs-CRP were measured on days 0, 10, and 21. RESULTS: The β-glucan group showed significantly higher serum levels of IL-12 on day 21 compared to the control group. Infection frequency and duration of mechanical ventilation were significantly lower in the β-glucan group. A significant difference was found in the Sequential Organ Failure Assessment (SOFA) score in favor of the β-glucan group. No difference was found in the serum levels of hs-CRP, length of ICU stay, occurrence of infection, and mortality rates between the two groups. CONCLUSION: β-glucan may increase serum levels of IL-12, shorten the duration of mechanical ventilation, and reduce organ failure in critically ill multiple-trauma patients. © 2018 Turkish Association of Trauma and Emergency Surgery

Cancer metastasis, genetic and microenvironmental factors of distant tissue: a review article

Cancer is one of the main reasons of mortality worldwide, and more than 90 percent of cancer deaths are due to metastasis. Although primary tumors are curable using chemical adjuvant therapy or surgery, metastatic tumors are mostly incurable. This resistance shows the high rate of mortality among patients with metastatic disease. Being a sequential event, metastasis is a subtle and intricate process in which tumor cells undergo a plenty of changes and acquire the capacity of migration, invasion, survival and self-renewal which all are necessary for metastasis to happen. The key point in recognition and cure in invasive cancers is to identify critical genes, proteins and pathways involved, and show their relation with each other and the disease. Forming metastasis needs favorable genetic and microenvironmental elements of tumor cells and distant tissue, respectively. Unfavorable conditions in each steps of this process lead to arresting metastasis and subsequent dormancy, which is the most important phenomenon in relapse. In this review, benefiting from tens of reliable and recently identified data and personal experiences, it has been tried to draw new patterns associated with metastasis for further investigation. Determining genes, proteins and microenvironmental factors that affect metastasis, in a sequential manner, can help better understanding of this lethal process and subsequently a prosperous treatment

The importance of circulating tumor cells and tumor models in future of cancer therapy

Development of new technologies is taking cancer research on a new journey in which plenty of mysterious aspects of cancer biology are being unraveled. To defeat cancer, we first need to understand the biology of this smart complex system, which often hijacks several programs to proliferate, invade, escape the immune system and colonize distant organs. Therefore, studying cancer cells in every step of tumor development (including primary tumor formation, invasion, circulation and metastatic colonization) is absolutely essential. Analysis of human-derived cancer models in primary site, circulation or metastatic lesions outside their host is one of the most promising ways to understand these complexities. The most common currently used and more recently developed cancer cell lines consist of primary patient-derived tumor xenograft (PDTX), circulating tumor cells isolation and analyzes, and primary tumor organoids. In this chapter we provide a brief update of some of the most important advances in studying and treatment of cancer using new technologie

Crosstalk between breast cancer stem cells and metastatic niche: Emerging molecular metastasis pathway?

Metastatic colonization represents the final step of metastasis, and is the major cause of cancer mortality. Metastasis as an "inefficient" process requires the right population of tumor cells in a suitable microenvironment to form secondary tumors. Cancer stem cells are the only capable population of tumor cells to progress to overt metastasis. On the other hand, the occurrence of appropriate microenvironmental conditions within the target tissue would be critical for metastasis formation. Metastatic niche seems to be the specialized microenvironment to support tumor initiating cells at the distant organ. Master regulators not only determine cancer stem cell state, but also may have regulatory roles in metastatic niche elements. Meanwhile, both cancer stem cell and metastatic niche may function like two sides of the metastatic coin. Hypoxia inducible factors have multiple roles in regulation of both sides of this coin. TGF-β superfamily, also, have been considered as master regulators of epithelial to mesenchymal transition and metastasis and may play crucial roles in regulation of metastatic niche as well. In this regard, we hypothesize the presence of a possible emerging molecular pathway in the biological process of breast cancer metastasis. In this process, non-Smad TGF-β-induced metastasis connects cancer stem cell and metastatic niche formation through a central path, "Metastasis Pathway". © 2013 International Society of Oncology and BioMarkers (ISOBM)

SLUG and SOX9 Cooperatively Regulate Tumor Initiating Niche Factors in Breast Cancer

Presence of tumor initiating cells and a proper niche is essential for metastatic colonization. SLUG and SOX9 transcription factors play essential roles in induction and maintenance of tumor initiating capacity in breast cancer cells. On the other hand, Tenascin-C and Periostin are crucial factors in metastatic niche that support tumor initiating capability in breast cancer. In this study, regulatory effect of SLUG and SOX9 transcription factors on the expression of Tenascin-C and Periostin was examined. SLUG and SOX9 were overexpressed and knocked-down in MCF7 and MDA-MB-231 cells, respectively. The cells as little and highly invasive breast cancer-derived cells were infected by inducing and shRNA lentivirus constructs. Then, Tenascin-C and Periostin as well as SLUG and SOX9 expression levels were measured in the cells via Real-Time PCR. Simultaneous overexpression of SLUG and SOX9 significantly induced Tenascin-C and Periostin expression. SLUG and SOX9 knock-down also significantly reduced the expression of Tenascin-C and Periostin. In this analysis Periostin showed the most deviation in both up- and down-regulation levels. This regulatory effect might shed light to a crosstalk between factors involved in the tumor initiating capacity and metastatic niche of the breast cancer. © 2015, Springer Science+Business Media Dordrecht

A novel mutation pattern of kidney anion exchanger 1 gene in patients with distal renal tubular acidosis in Iran

Introduction. Mutations of the anion exchanger 1 (AE1) gene encoding the kidney anion exchanger 1 can result in autosomal dominant or autosomal recessive form of distal renal tubular acidosis (DRTA). This study aimed to report deletion mutations of the AE1 and its impact on Iranian children with DRTA. Materials and Methods. Twelve children with DRTA referred to Ali Asghar Children Hospital were investigated for all AE1 gene exons through polymerase chain reaction amplification, DNA sequencing, and bioinformatics analysis. Results. Eleven of 12 patients (91.7) showed an alteration in AE1 gene with a real hot spot in its exons 11 or 15. Homozygote and heterozygote deletions were confirmed in exon 15 in 5 (41.7) and 3 (25.0), respectively. Two patients (16.7) showed homozygote deletions in exon 11 of AE1 gene, and 1 patient (8.3) showed point mutation in exon 11. The 3-dimensional structures of the native and these mutant kidney AE1 proteins were determined by the multitemplate method using the Phyre and Hidden Markov Model algorithms. Conclusions. Parents� consanguinity of these patients reveals that cousins are at a high risk for DRTA. This study is considered as a pilot study showing the importance of AE1 mutations in Iranian children with DRTA and further studies is recommended in this geographic region of the world. These models suggest that alteration in the structures leads to alteration in function and change in the current role of AE1. © 2015, Iranian Society of Nephrology. All Rights Reserved

A gene regulatory network to control EMT programs in development and disease

The Epithelial to Mesenchymal Transition (EMT) regulates cell plasticity during embryonic development and in disease. It is dynamically orchestrated by transcription factors (EMT-TFs), including Snail, Zeb, Twist and Prrx, all activated by TGF-β among other signals. Here we find that Snail1 and Prrx1, which respectively associate with gain or loss of stem-like properties and with bad or good prognosis in cancer patients, are expressed in complementary patterns during vertebrate development and in cancer. We show that this complementarity is established through a feedback loop in which Snail1 directly represses Prrx1, and Prrx1, through direct activation of the miR-15 family, attenuates the expression of Snail1. We also describe how this gene regulatory network can establish a hierarchical temporal expression of Snail1 and Prrx1 during EMT and validate its existence in vitro and in vivo, providing a mechanism to switch and select different EMT programs with important implications in development and disease

MicroRNAs establish the right-handed dominance of the heart laterality pathway in vertebrates

Despite their external bilateral symmetry, vertebrates have internal left/right (L/R) asymmetries required for optimal organ function. BMP-induced epithelial to mesenchymal transition (EMT) in the lateral plate mesoderm (LPM) triggers L/R asymmetric cell movements toward the midline, higher from the right, which are crucial for heart laterality in vertebrates. However, how the L/R asymmetric levels of EMT factors are achieved is not known. Here, we show that the posterior-to-anterior Nodal wave upregulates several microRNAs (miRNAs) to transiently attenuate the levels of EMT factors (Prrx1a and Snail1) on the left LPM in a Pitx2-independent manner in the fish and mouse. These data clarify the role of Nodal in heart laterality and explain how Nodal and BMP exert their respective dominance on the left and right sides through the mutual inhibition of their respective targets, ensuring the proper balance of L/R information required for heart laterality and morphogenesis.This work was supported by grants from the European Research Council (ERC AdG 322694), the Spanish Ministries of Economy, Industry, and Competitiveness (MINEICO-BFU2014-53128-R) and of Science, Innovation and Universities (MICIU RTI2018-096501-B-I00), and Generalitat Valenciana (PROMETEOII/2017/150) to M.A.N. The latter three grants are co-financed by the European Regional Development Fund, ERDF. L.R. was a holder of a Juan de la Cierva Formación postdoctoral scholarship. N.C. and F.G.-A. are recipients of PhD Student scholarships (FPU and FPI, respectively). The three scholarships are from MINEICO and MECD. M.A.N. acknowledges financial support from the Spanish State Research Agency (AEI), through the BFU and RTI grants as indicated above and also the “Severo Ochoa” Programme for Centres of Excellence in R&D (SEV-2017-0273) to Instituto de Neurociencias (IN).Peer reviewe