International Journal of Current Research and Review
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IJCRR - Vol 04 Issue 05, March, 2012

Pages: 58-62

Date of Publication: 30-Nov--0001


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SALIVARY FERRITIN - A CONCISE UPDATE ON CURRENT CONCEPTS

Author: Nithya Jagannathan, Prasanna Neelakantan, Pratibha Ramani, Priya Premkumar, Anuja Natesan, Herald J. Sherlin

Category: Healthcare

Abstract:Ferritin is a ubiquitous and highly conserved iron-binding protein. Increasingly, perturbations
in cellular iron and Ferritin are emerging as an important element in the pathogenesis of disease. Ferritin levels seem to reflect the magnitude of iron stores in the body and decreased or increased serum Ferritin levels are used as a marker for anaemia and iron overload disorders. Serum Ferritin was discovered in the 1930s, and was developed as a clinical test in the 1970s. However, the presence of Ferritin in saliva was not documented until 1984. The salivary Ferritin values are usually higher than the iron stores present in the body and these values are subject to change in iron deficiency anaemia, iron overload disorders and protein malnutrition.
The biological system maintains the salivary Ferritin levels at a higher level, probably for the
iron dependent enzymatic functions of the saliva, thus conserving the iron through saliva. This paper gives an update of Ferritin and its presence in saliva and various mechanisms which cause a rise in Ferritin.

Keywords: saliva, Ferritin, iron deficiency, anaemia, malnutrition

Full Text:

INTRODUCTION
Although essential for most forms of life, too much iron is harmful. To cope with these antagonistic phenomena an ironstorage molecule, Ferritin, has evolved. Ferritin evolved as the only protein able to solve the problem of iron/oxygen chemistry and metabolism1 . Aquated, ferrous iron is oxidized with oxygen to concentrate as many as 4000 iron atoms as a solid oxomineral in the centre of the Ferritin protein2 . Ferritin is a highly specialized ubiquitous iron storage protein and has generally been thought to function as a “housekeeper” storage protein which can release iron required for cellular proliferation and metabolic renewal3 . It stores iron and releases it in a controlled fashion. Ferritin levels seem to reflect the magnitude of iron stores in the body and decreased or increased Ferritin levels are used as a marker for anaemia and iron overload disorders4 . Ferritins are part of the extensive „Ferritin-like superfamily? of proteins within which all members are believed to share the characteristic fourhelical bundle structural motif5 . Ferritin is found mainly in the cytoplasm of the reticuloendothelial cells, liver cells, and to a lesser extent in the developing red cell precursors in the bone marrow6.

Historical Perspective: Ferritin, an iron storage protein was initially discovered by Laufberger and colleagues in 1937, who isolated a new protein from horse spleen which contained up to 23% by dry weight of iron. Discovered early in the 20th century, Ferritin began yielding its secrets at the century?s end7 . Pauline, in 1952 was the first to introduce to Ferritin crystals in the laboratory of Nobel laureate Dorothy Hodhkins.and he isolated Ferritin from horse spleen in 1957 in the old Scala Cinema in Sheffield, UK. The appearance of Ferritin in human serum was documented several years thereafter8 . Since 1972, when the first sensitive immunoassay for Ferritin was described, there have been an impressive number of studies on serum Ferritin concentration in normal and disease states, and the clinical usefulness of the serum Ferritin assay in evaluating body iron status is now well established9 . Serum Ferritin continues to be a useful and convenient method of assessing the iron storage, although it is now known that many additional factors, including inflammation, infection and malignancy may elevate serum Ferritin and complicate the interpretation of this value10. The presence of Ferritin in Saliva has been documented by Agarwal and coworkers in 198411 . Structural Aspects of Ferritin As early as 1944, Granick and Hahn claimed that the iron-cores were particulate 'micellar' in form12. Farant in 1954 demonstrated the structure of Ferritin electron microscopically and considered it to be a tetrad with four subunits, the iron being deposited at the four corners of a cube with a diameter of about 55 A13 . In 1960, Kerr and Muir described the ironcore of Ferritin as consisting of six subunits arranged at the apices of a regular octahedron14. The growth of threedimensional structure of Ferritin suggested that tetragonal crystals were grown for apoFerritin and Ferritin co-crystallized with apoFerritin in an orthorhombic form15 . Human Ferritin is a globular protein complex and a high molecular weight iron compound keeping iron in a soluble and non-toxic form. The protein shell consists of a component named apoFerritin with a molecular weight of approximately 4,50,000 Daltons. It is composed of 20-24 subunits which forms a hollow sphere of internal diameter about 70A and is made up of heart (H) and liver (L) subunits, with molecular masses of 21 kDa and 19 kDa, respectively16, 17. In the centre core of this shell, these is presence of variable number of iron atoms up to about 4500 , accommodated as a microcrystalline core, or micelle, of hydrated ferric phosphate(FeOOH)8 (FeO:OP03H2). It consisting of 24 protein subunits and is the primary intracellular iron-storage protein18,19. Iron may compromise upto 20% of the molecule which may have a molecular weight as high as 9,00,00020 . Salivary Ferritin: Saliva is a complex fluid composed of a wide variety of organic and inorganic substances in the form of protein, various enzymes, sodium, potassium, thiocyanates and some minerals such as iron, copper and chromium. These minerals are present in saliva at a gradient which is comparable with serum. They collectively act to modulate the oral environment21 . a. Salivary Ferritin in Iron deficiency anaemia Agarwal and coworkers observed that saliva contains Ferritin and changes in Ferritin levels have been observed in iron deficiency and its levels in saliva were much higher than the normal11. Lagunoff and Benditt in 1963 first observed Ferritinlike particles in occasional mast-cell granules and suggested that Ferritin may be taken up as such by the granules and then transformed into another form. This was the first step in the discovery of salivary Ferritin22 .

The exact mechanism by which anaemia caused a rise in salivary Ferritin is not exactly known. The levels of salivary Ferritin in normal subjects is 95-105 µg/ dl whereas the levels increases up to 130 – 170 µg/ dl in iron deficiency anaemia23 . However, it may be speculated that the iron dependent enzymatic functions of the saliva also help in the conservation of iron through saliva of iron deficient patients 23 . Changes in Salivary Ferritin occur even before the hematological changes and hence these measurements are clinically significant in monitoring the iron status24 . Other possibilities include endocytosis of Ferritin by the ducts of salivary glands and its excretion into the saliva and presence of high molecular weight iron binding properties of saliva22,25. Internalization of Ferritin in the intercalated ducts in the form of lysosomes in the parotid duct could serve as a possible mechanism for the increased salivary levels. This mechanism hitherto has been established in rats, but evidence is not conclusive in human beings. This may also be the mechanism for alterations in the proteins in saliva before it reaches the oral cavity 25 . Furthermore saliva possesses a marked iron binding ability and the high molecular weight iron binding substance in saliva might have a function in health and disease, both because of its molecular weight and its resistance to acid peptic digestion26 . Another possible mechanism may also be attributed to the increased salivary manganese levels which inhibit the salivary Ferritin transport leading to its retention thereby raising the salivary Ferritin in iron deficiency anaemia. However, the scanty literature on this aspect does not allow us to draw an exact pathogenesis for the rise of Ferritin27. Activity of the enzyme arginase, in human saliva has been found to be more in serum. It is possible that iron and manganese share a common cellular transport mechanism and thus excesses of one element inhibit transport of the other 26 . Ferritin is usually present in the saliva of all men with iron deficient anaemia and in 73% of iron deficient women. In normal individuals, salivary Fe3+ are met only in 50% of men and 32% of women27 . b. Salivary Ferritin in Iron Overload disorders: The salivary ferritin shows a considerable rise in iron overload disorders. However the ratio of serum and salivary ferritin remains constant, demonstrating that there is a proportional rise in salivary ferritin and serum ferritin maintaining a constant value23 . c. Salivary Ferritin in Protein Energy Malnutrition: The salivary Ferritin is remarkably reduced in grade I PEMand shows a mild decrease in grade III PEM. Whether the change is basically related to protein deficiency or is due to low iron stores in these patients is difficult to say11 .

CONCLUSION
The role of saliva as a diagnostic tool has been a topic of interest in the recent years. Salivary Ferritin would add as a monitoring tool in diagnosis of iron deficiency anaemia and will aid to improve the quality of life of iron deficient individuals. Thus the presence of Ferritin in saliva could serve as a diagnostic tool in various field works and epidemiologiacal surveys.

ACKNOWLEDGEMENT
I acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. I am also grateful tothe editors of all those articles, and books from where the literature for this article has been reviewed and discussed. The authors thank Dr. Prasanna Neelakantan, Endodontist, Saveetha Dental College for his contribution in preparing the manuscript.

References:

1. G. C. Ford, P. M. Harrison, D. W. Rice, J. M. A. Smith, A. Treffry, J. L. White, J. Yariv; Ferritin: Design and Formation of an Iron-Storage Molecule; Philos Trans R Soc Lond B Biol Sci. 1984;304 (1121): 551-65.

2. E.C.Theil, Ferritin: At the Crossroads of Iron and Oxygen Metabolism, J Nutri. 2003 (Supplementary issue); 1549S – 1553S

3. A Giordani, J Haigle, P Leflon, A Risler, S Salmon, M Aubailly, J C Maieère, R Santus, P Morliere, Contrasting effects of excess ferritin expression on the iron-mediated oxidative stress induced by tert-butyl hydroperoxide or ultraviolet-A in human fibroblasts and keratinocytes, J Photochem Photobiol B,2000; 54(1): 43-54

4. G Balla, H S. Jacob, J Balla, M Rosenberg, K Nath, Freadpple, J W. Eaton, Gregory M, Ferritin: A Cytoprotective Antioxidant Strategem of Endothelium, J Biol Chem, 1992; 265 (25): 18148-18153

5. SC Andrews , The Ferritin-like superfamily: evolution of the biological iron storeman from a rubrerythrin-like ancestor, Biochimica et Biophysica Acta, 2010; 1800(8): 691-705.

6. Jacobs, F. Miller, M. Worwood, M.R. Beamish, Ferritin in the serum of normal subjects and Patients with Iron Deficiency and Iron Overload, Brit Med J, 1972; 4: 206-208

7. W. Wang, Serum ferritin: Past, present and future, Biochim. Biophys. Acta , 2010; 8:760-769

8. M. Worwood, Iron in Biochemistry and Medicine, II In: A. a. W., M. Jacobs (Eds.), , Academic Press, London; 1980: 204–244.

9. G.M. Addison, M.R. Beamish, C.N. Hales, M. Hodgkins, A. Jacobs, P. Llewellin, An immunoradiometric assay for ferritin in the serum of normal subjects and patients with iron deficiency and iron overload, J. Clin. Pathol, 1972; 25: 326–329.

10. G. Zandman-Goddard, Y. Shoenfeld, Ferritin in autoimmune diseases, Autoimmun. Rev.2007; 6: 457–463.

11. PKAgarwal, KN Agarwal, DK Agarwal, Biochemical changes in saliva of malnourished children, Am J Clin Nutr,1984; 39(2): 181-184

12. Granick, S, Ferritin. IV. Occurrence and immunological properties of ferritin. J. Biol. Chem. 1943; 149: 157– 16

13. J.L Farant , An electron microscopic study of ferritin, Biochimica et Biophysica Acta, 1954; 13: 569-576

14. D.N.S. Kerr, A.R. Muir, A demonstration of the structure and disposition of ferritin in the human liver cell, Journal of Ultrastructure Research, 1960; 3(3): 313-319

15. Vekilov PG, Feeling-Taylor AR, Yau ST, Petsev D, Solvent entropy contribution to the free energy of protein crystallization, Acta Crystallogr D Biol Crystallogr, 2002 ; 58:1611-6.

16. Harrison, P. M. In Iron Metabolism (Gross, F., ed.), Springer-Verlag, Berlin; 1964: 40.

17. M. Worwood, J.D. Brook, S.J. Cragg, B. Hellkuhl, B.M. Jones, P. Perera, S.H. Roberts, D.J. Shaw, Assignment of human ferritin genes to chromosomes 11 and 19q13.3– 19qter, Hum. Genet. 1985; 69: 371–374.

18. Granick, S. Ferritin: Its Properties and Significance for Iron Metabolism, Chem. Rev, 1946; 38: 379

19. Haggis, G. H. The iron oxide core of the ferritin molecule, J. Mol. Biol, 1965; 14(2), 598

20. A. Jacobs, F. Miller, M. Worwood, M. R. Beamish, C. A. Wardrop, Ferritin in the Serum of Normal Subjects and Patients with Iron Deficiency and Iron Overload Brit Med J, 1972; 4: 206-208

21. Jenkins GN, Saliva In: Physiology and biochemistry of the mouth, 4th edition, 1978; 284-359

22. Lagunoff, D, E . P. Benditt, Proteolytic enzymes of mast cells . Ann . N. Y. Acad. Sci. 1963; 103 :185

23. O.P.Mishra, Salivary Iron status in children with iron deficiency and iron overload, J Trop Ped, 1992 ; 38 (2) : 64-67

24. JS Rennie, DG MacDonald, JH Dagg . Iron and the oral epithelium: a review. J R Soc Med 1984; 77:602-607.

25. A. R. Hand, R. Coleman, M. R. Mazariegos, J. Lustmann, L. V. Otti , Endocytosis of Proteins by Salivary Gland Duct Cells ,J Dent Res ,1987; 66(2):412-41

26. Peter L. Reilly, Peter S. Davis, Donald J. Deller. Iron Binding Properties of Saliva, Nature, 1968; 217: 68

27. Rafik GS, Lyudmila IL, Tamara IV, Mikhail GV, Electron paramagnetic resonance in biochemistry and medicine; 2001 Feb: 111-112

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One article from every issue is selected for the ‘Best Article Award’. Authors of selected ‘Best Article’ are rewarded with a certificate. IJCRR Editorial Board members select one ‘Best Article’ from the published issue based on originality, novelty, social usefulness of the work. The corresponding author of selected ‘Best Article Award’ is communicated and information of award is displayed on IJCRR’s website. Drop a mail to editor@ijcrr.com for more details.

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This award is instituted to encourage women researchers to publish her work in IJCRR. Women researcher, who intends to publish her research work in IJCRR as the first author is eligible to apply for this award. Editorial Board members decide on the selection of women researchers based on the originality, novelty, and social contribution of the research work. The corresponding author of the selected manuscript is communicated and information is displayed on IJCRR’s website. Under this award selected women, the author is eligible for publication incentives. Drop a mail to editor@ijcrr.com for more details.

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Best Article Award

A Study by Amr Y. Zakaria et al. entitled "Single Nucleotide Polymorphisms of ATP-Binding Cassette Gene(ABCC3 rs4793665) affect High Dose Methotrexate-Induced Nephrotoxicity in Children with Osteosarcoma" is awarded Best Article for Vol 13 issue 19
A Study by Kholis Ernawati et al. entitled "The Utilization of Mobile-Based Information Technology in the Management of Dengue Fever in the Community Year 2019-2020: Systematic Review" is awarded Best Article for Vol 13 issue 18
A Study by Bhat Asifa et al. entitled "Efficacy of Modified Carbapenem Inactivation Method for Carbapenemase Detection and Comparative Evaluation with Polymerase Chain Reaction for the Identification of Carbapenemase Producing Klebsiella pneumonia Isolates" is awarded Best Article for Vol 13 issue 17
A Study by Gupta R. et al. entitled "A Clinical Study of Paediatric Tracheostomy: Our Experience in a Tertiary Care Hospital in North India" is awarded Best Article for Vol 13 issue 16
A Study by Chandran Anand et al. entitled "A Prospective Study on Assessment of Quality of Life of Patients Receiving Sorafenib for Hepatocellular Carcinoma" is awarded Best article for Vol 13 issue 15
A Study by Rosa PS et al. entitled "Emotional State Due to the Covid – 19 Pandemic in People Residing in a Vulnerable Area in North Lima" is awarded Best Article for Vol 13 issue 14
A Study by Suvarna Sunder J et al. entitled "Endodontic Revascularization of Necrotic Permanent Anterior Tooth with Platelet Rich Fibrin, Platelet Rich Plasma, and Blood Clot - A Comparative Study" is awarded Best Article for Vol 13 issue 13
A Study by Mona Isam Eldin Osman et al. entitled "Psychological Impact and Risk Factors of Sexual Abuse on Sudanese Children in Khartoum State" is awarded Best Article for Vol 13 issue 12
A Study by Khaw Ming Sheng & Sathiapriya Ramiah entitled "Web Based Suicide Prevention Application for Patients Suffering from Depression" is awarded Best Article for Vol 13 issue 11
A Study by Purushottam S. G. et al. entitled "Development of Fenofibrate Solid Dispersions for the Plausible Aqueous Solubility Augmentation of this BCS Class-II Drug" is awarded Best article for Vol 13 issue 10
A Study by Kumar S. et al. entitled "A Study on Clinical Spectrum, Laboratory Profile, Complications and Outcome of Pediatric Scrub Typhus Patients Admitted to an Intensive Care Unit from a Tertiary Care Hospital from Eastern India" is awarded Best Article for Vol 13 issue 09
A Study by Mardhiah Kamaruddin et al. entitled "The Pattern of Creatinine Clearance in Gestational and Chronic Hypertension Women from the Third Trimester to 12 Weeks Postpartum" is awarded Best Article for Vol 13 issue 08
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A Study by Gainneos PD et al. entitled "A Comparative Evaluation of the Levels of Salivary IgA in HIV Affected Children and the Children of the General Population within the Age Group of 9 – 12 Years – A Cross-Sectional Study" is awarded Best Article of Vol 13 issue 05 Special issue on Recent Advances in Dentistry for better Oral Health
A Study by Alkhansa Mahmoud et al. entitled "mRNA Expression of Somatostatin Receptors (1-5) in MCF7 and MDA-MB231 Breast Cancer Cells" is awarded Best Article of Vol 13 issue 06
A Study by Chen YY and Ghazali SRB entitled "Lifetime Trauma, posttraumatic stress disorder Symptoms and Early Adolescence Risk Factors for Poor Physical Health Outcome Among Malaysian Adolescents" is awarded Best Article of Vol 13 issue 04 Special issue on Current Updates in Plant Biology to Medicine to Healthcare Awareness in Malaysia
A Study by Kumari PM et al. entitled "Study to Evaluate the Adverse Drug Reactions in a Tertiary Care Teaching Hospital in Tamilnadu - A Cross-Sectional Study" is awarded Best Article for Vol 13 issue 05
A Study by Anu et al. entitled "Effectiveness of Cytological Scoring Systems for Evaluation of Breast Lesion Cytology with its Histopathological Correlation" is awarded Best Article of Vol 13 issue 04
A Study by Sharipov R. Kh. et al. entitled "Interaction of Correction of Lipid Peroxidation Disorders with Oxibral" is awarded Best Article of Vol 13 issue 03
A Study by Tarek Elwakil et al. entitled "Led Light Photobiomodulation Effect on Wound Healing Combined with Phenytoin in Mice Model" is awarded Best Article of Vol 13 issue 02
A Study by Mohita Ray et al. entitled "Accuracy of Intra-Operative Frozen Section Consultation of Gastrointestinal Biopsy Samples in Correlation with the Final Histopathological Diagnosis" is awarded Best Article for Vol 13 issue 01
A Study by Badritdinova MN et al. entitled "Peculiarities of a Pain in Patients with Ischemic Heart Disease in the Presence of Individual Combines of the Metabolic Syndrome" is awarded Best Article for Vol 12 issue 24
A Study by Sindhu Priya E S et al. entitled "Neuroprotective activity of Pyrazolone Derivatives Against Paraquat-induced Oxidative Stress and Locomotor Impairment in Drosophila melanogaster" is awarded Best Article for Vol 12 issue 23
A Study by Habiba Suhail et al. entitled "Effect of Majoon Murmakki in Dysmenorrhoea (Usre Tams): A Standard Controlled Clinical Study" is awarded Best Article for Vol 12 issue 22
A Study by Ghaffar UB et al. entitled "Correlation between Height and Foot Length in Saudi Population in Majmaah, Saudi Arabia" is awarded Best Article for Vol 12 issue 21
A Study by situs slot and Siti Sarah Binti Maidin entitled "Sleep Well: Mobile Application to Address Sleeping Problems" is awarded Best Article for Vol 12 issue 20
A Study by Avijit Singh et al. situs slot "Comparison of Post Operative Clinical Outcomes Between “Made in India” TTK Chitra Mechanical Heart Valve Versus St Jude Mechanical Heart Valve in Valve Replacement Surgery" is awarded Best Article for Vol 12 issue 19
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A Study by Jabbar Desai et al. entitled "Prevalence of Obstructive Airway Disease in Patients with Ischemic Heart Disease and Hypertension" is awarded Best Article for Vol 12 issue 17
A Study by Juna Byun et al. entitled "Study on Difference in Coronavirus-19 Related Anxiety between Face-to-face and Non-face-to-face Classes among University Students in South Korea" is awarded Best Article for Vol 12 issue 16
A Study by Sudha Ramachandra & Vinay Chavan entitled "Enhanced-Hybrid-Age Layered Population Structure (E-Hybrid-ALPS): A Genetic Algorithm with Adaptive Crossover for Molecular Docking Studies of Drug Discovery Process" is awarded Best article for Vol 12 issue 15
A Study by Varsha M. Shindhe et al. entitled "A Study on Effect of Smokeless Tobacco on Pulmonary Function Tests in Class IV Workers of USM-KLE (Universiti Sains Malaysia-Karnataka Lingayat Education Society) International Medical Programme, Belagavi" is awarded Best article of Vol 12 issue 14, July 2020
A study by Amruta Choudhary et al. entitled "Family Planning Knowledge, Attitude and Practice Among Women of Reproductive Age from Rural Area of Central India" is awarded Best Article for special issue "Modern Therapeutics Applications"
A study by Raunak Das entitled "Study of Cardiovascular Dysfunctions in Interstitial Lung Diseas epatients by Correlating the Levels of Serum NT PRO BNP and Microalbuminuria (Biomarkers of Cardiovascular Dysfunction) with Echocardiographic, Bronchoscopic and HighResolution Computed Tomography Findings of These ILD Patients" is awarded Best Article of Vol 12 issue 13 
A Study by Kannamani Ramasamy et al. entitled "COVID-19 Situation at Chennai City – Forecasting for the Better Pandemic Management" is awarded best article for  Vol 12 issue 12
A Study by Muhammet Lutfi SELCUK and Fatma situs slot entitled "Distinction of Gray and White Matter for Some Histological Staining Methods in New Zealand Rabbit's Brain" is awarded best article for  Vol 12 issue 11
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A Study by K. Krupashree et. al. entitled "Protective Effects of Picrorhizakurroa Against Fumonisin B1 Induced Hepatotoxicity in Mice" is awarded best article for issue Vol 10 issue 20
A study by Mithun K.P. et al "Larvicidal Activity of Crude Solanum Nigrum Leaf and Berries Extract Against Dengue Vector-Aedesaegypti" is awarded Best Article for Vol 10 issue 14 of IJCRR
A study by Asha Menon "Women in Child Care and Early Education: Truly Nontraditional Work" is awarded Best Article for Vol 10 issue 13
A study by Deep J. M. "Prevalence of Molar-Incisor Hypomineralization in 7-13 Years Old Children of Biratnagar, Nepal: A Cross Sectional Study" is awarded Best Article for Vol 10 issue 11 of IJCRR
A review by Chitra et al to analyse relation between Obesity and Type 2 diabetes is awarded 'Best Article' for Vol 10 issue 10 by IJCRR. 
A study by Karanpreet et al "Pregnancy Induced Hypertension: A Study on Its Multisystem Involvement" is given Best Paper Award for Vol 10 issue 09
Late to bed everyday? You may die early, get depression situs slot
Egg a day tied to lower risk of heart disease situs slot
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A Study by Ese Anibor et al. "Evaluation of Temporomandibular Joint Disorders Among Delta State University Students in Abraka, Nigeria" from Vol 13 issue 16 received Emerging Researcher Award


A Study by Alkhansa Mahmoud et al. entitled "mRNA Expression of Somatostatin Receptors (1-5) in MCF7 and MDA-MB231 Breast Cancer Cells" from Vol 13 issue 06 received Emerging Researcher Award


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