CC BY
25
DOI: http://dx.doi.org/10.20534/ESR-16-11.12-49-52
Mavlyanova Shahnoza Zakirovna, The first Republic Specialised Scientific-Practical Medical Centre of Dermatology and Venereology of MinH of the Republic of Uzbekistan Boboev Abdukadir Tuhtabaevich, The first Republic Specialised Scientific-Practical Medical Centre of Dermatology and Venereology of MinH of the Republic of Uzbekistan. Gulyamova Gulchekhra Shuhratovna, The first Republic Specialised Scientific-Practical Medical Centre of Dermatology and Venereology of MinH of the Republic of Uzbekistan. Yunusova Zarina Serverovna, The first Republic Specialised Scientific-Practical Medical Centre of Dermatology and Venereology of MinH of the Republic of Uzbekistan. Mullahanov Javlon Bohodirovich, The second scientific research institute of Haematology and blood transfusion of MinH of the Republic of Uzbekistan.
E-mail: gulyamova.1971@mail.ru
The role of genes enzymes xenobiotics in the mechanisms of formation of heavy severity level of allergic dermatosis
Abstract: The article presents the results of molecular genetic studies of genes of enzymes of biotransformation of xenobiotics in patients with allergic dermatoses. The study involved 88 patients with allergic dermatoses in age from 5 to 67 years. Results studies have shown that patients with allergic dermatoses observed increased incidence of combined null genotype (GSTM10/0 + GSTT10/0) compared to the population sample (6.8% and 4.1 suitability%) The obtained data indicates that of the Uzbek population of individuals with combined null genotype enzyme genes GSTM1 and GSTT1 xenobiotics tend to risk of severe allergic severity.
Keywords: allergic skin diseases, genes of enzymes of biotransformation of xenobiotics, gene polymorphism, clinic.
Allergic dermatosis occupies one of the leading places in structure of the general disease of a skin and hypodermic cellular tissue and makes 56,2% among skin diseases. [Mavlyanova S. Z., 2014, Nazarov A. A. 2008] On the basis of formation of allergic dermatosis lays interaction of various genetic factors with environmental factors. One of the effective approaches to studying of mechanisms of allergic dermatosis development is connected with research of the genes, products which can be expressly or by implication involved in development of the given pathology.
The purpose of our researches is studying of polymorphism of gene enzymes of xenobiotics biotransformation in patients with allergic diseases of a skin.
Material and research methods: Object and subject of research were the patients with allergic dermatosis (AlD), samples of DNA of sick and healthy donors, gluten transfusion genes GSTM1 (1p13.3), GSTT1 (22q11.2).
88 patients have been included in research with AlD at the age from 5 till 67 were observed on the basis of clinic RSSNPMC DandV of MinH of the Republic of Uzbekistan. From them 41 — women, 47 — men. The diagnosis at all patients is confirmed by results of clinical inspection (DISS) and laboratory researches. All patients were surveyed, observed and passed treatment in branch of dermatology RSSNPMC D and V. (DNA) carried out
molecular-genetic inspection ofbiomaterials on the basis of department of molecular medicine and cellular technologies of scientific research institute of haematology and blood transfusion of MinH of the Republic of Uzbekistan.
At carrying out of genetic researches as comparison group population control was used, which has been presented by samples of DNA (n=72) conditionally healthy donors (without any signs of atopic diseases) from bank of DNA of the given department.
The statistical analysis of results is spent with use of a package of statistical programs «OpenEpi 2009, Version 2.3».
Electric phoregramme of genes detection GSTM1 and GSTT1 (459 items h. — gene GSTT1, 375 items h. — ^ — yA|a0v, 213 o. v. — GSTM1)
Results of research. On age aspect patients with AlD up to 14 years old have made — 13, 15-20 year olds — 12, 21-30-17, 31-40 year olds — 12, 41-50-10 and over 50 years old — 24 patients. Under the clinical form allergic dermatosis has been diagnosed accordingly among 88 patients, 49 patients with atopic dermatitis, 28 patients with nettle rush, 11 patients with allergic dertatitis. Taking into account index AHfflC moderate severity level is diagnosed for 10 patients AlD (on the average 24,6+1,8 point) and 78 — heavy severity level (29,3+0,5 point) diseases.
Figure 1. Electric phoregramme of genes detection GSTM1 and GSTT1 (459 items h. — gene GSTT1, 375 items h. — | — globin, 213 o. v. — GSTM1)
The characteristic of a genetic marker and sequence synthesised of oligoprimers are resulted in table 1.
Table 1. - Sequence of oligonucleotides primers used for carrying out n^
№ Gene, localisation Polymorphism Structure of oligoprimers
1 GSTM1 (1p13.3) deletion F 5-'GAACTCCCTGAAAAGCTAAAGC-3' R 5-'GTTGGGCTCAAATATAGGGTGG-3'
2 GSTT1 (22q11.2) deletion F 5 '-TTCCTTACTGGTCCTCACATCTC-3 ' R 5-' TCACCG GATCATGG CCAG CA- 3'
Results of molecular-genetic researches of polymorphism certain features of deletional polymorphism GSTM1 and GSTT1 of genes enzymes xenobiotics in patients with AlD have revealed (table 2).
Table 2. - Distribution frequency of alleles and polymorphism genotypes del/del genes GSTM1 and GSTT1 in groups of patients and the control
№ Groups Frequency of distribution of genotypes
GSTM1 «+» GSTM1 (0/0) GSTT1«+» GSTT1 (0/0)
*n % *n % *n % *n %
1 The basic group N=88 55 62.5 33 37.5 65 73.9 23 26.1
2 Contr. Group n=72 46 64.0 26 36.1 54 75.0 18 25.5
n - number of the surveyed patients; *n - number of the investigated chromosomes Apparently from table 2, in the basic group of patients it was observed the tendency to insignificant increase in frequency of nonfunctional genotype GSTM1 (0/0) in comparison with the control (37,5% against 36,1%) accordingly. The risk of development ofAlD in carriers of deletional genotype GSTM1 (0/0) has appeared in 1,1 times above in comparison with the individuals, having functional GSTM1 «+» a genotype. (OR=1.1; 95%CI 0). However calculation of frequencies of distribution of zero genotypes of gene GSTM1 between patients of AlD (the basic group) and the control has shown, statistically not significant distinctions (X2=0.3; n =0.1).
At the analysis of frequency of genotypes GSTT1 in group of patients of AlD following features are revealed. So in patients with AlD frequency functional GSTT1 +/+ a genotype in 1,01 times was less in comparison with indicators control healthy group and has made 73,9% in comparison with control healthy group, against 75.0% accordingly. Whereas frequency of zero genotypes GSTT10/0 in group of patients with AlD has made 26,1%, that in 1,1 times was above in comparison with indicators of the healthy faces, however the obtained given indicators did not reach level of statistically significant indicators (x2=0.03; P=0.9; OR=1.1; 95% CI0. 0.519 2.169).
70,6
80 70 60 50 40 30 20 10 0
GCTM1 + GSTM10/0 GSTT1+ GSTT10/0 Diagram 1. Indicators of distribution of genotypes 0BK in patients with AlD (%)
i Light Medium Heavy
So, frequency studying of alleles and genotypes of genes $BK taking into account severity level of allergic dermatosis drew the following features. (The diagram 1.)
As follows from the diagramme, frequency of functional and zero genotypes GSTM1 and GSTT1 most often came to light in patients with heavy and moderate severity level. Thus it is necessary
to notice, that in patients with AlD frequency not functional genotype GSTM1 «0/0» in 38,8% of cases and GSTT1 0/0 = 22,4% of cases basically met in patients from heavy severity level.
The obtained data testifies that deletional polymorphisms GSTM1 and GSTT1 can be independent markers of the raised risk of development of heavy severity level of AlD.
Table 3. - Frequency distribution of combined genotypes of deletional polymorphisms genes GSTM1 and GSTT1 in the investigated groups
Frequency of distribution of genotypes
Groups GSTM1 0/0 + GSTT1 0/0 GSTM1 0/0 + GSTT1«+» GSTT10/0+ GSTM1 «+» GSTM1 «+» + GSTT1«+»
n % n % n % n %
1 The basic group N=88 6 6,8 27 30,7 17 19,3 38 43,2
2 Contr. Group n=72 3 4.1 24 33.3 14 19.4 31 43.0
The note: *n — quantity of the surveyed patients
0/0 + 0/0: x2=0.5; P=0.4; 0R=1.7; 95%CI 0.4058, 6.979 (there is a tendency).
Heterozygotic genotypes: x2=0.1; n =0.9; 0R=1.0; 95% CI0.5221, 1.875.
Homozygotic genotypes: x2=0.1; n =0.9; 0R=1.0; 95% CI 0.5359, 1.885.
Apparently from table 3, among patients with AlD, individuals with combined functionally defective genotypes GSTM10/0+GSTT10/0 met more often, than in group of healthy faces (6,8% against 4,1%, accordingly; x 2=0.5; P=0.4; 0R=1.7; 95%CI 0). The obtained data testifies that individuals with zero genotypes of genes enzymes xenobiotics GSTM1 and
GSTT1 have a tendency to risk of allergic dermatosis development. Whereas, in combined variants — zero and functional genotypes of polymorphism of genes GSTM1 and GSTT1 between the investigated groups has not revealed statistically significant distinctions (p> 0.05).
Thus, results of research have shown, that in patients with allergic dermatosis the raised frequency of combined zero genotypes (GSTM10/0 + GSTT10/0) in comparison with population sample (6,8% and 4,1% accordingly) is marked. The obtained data testifies that in Uzbekistan individuals with combined zero genotypes of genes enzymes xenobiotics GSTM1 and GSTT1 have a tendency to risk of development of allergic dermatosis heavy severity level.
Refefrnces:
1. Aliev V. SH. Clinical and molecular-genetic aspects of an allergic rhinitis in Uzbekistan.//the autoreport doc. dissertation. - Tashkent -2012. - 33 с.
2. Alimhodzhaeva P.R, Karimov H. J., Muminova S. R. System engineering of molecular testing and the analysis of interrelation of poly-morphism-590S> Т gene IL4 with atopic dermatitis.//medical magazine of Uzbekistan. - No1. - 2012. - 19-21.
3. Bogomazov A. D. Ecological and population-demographic factors and their role in formation of a pathology of the children's population of Kursk area: the autoreport dissertation of medical sciences/Kursk, - 2005. - 22 p.
4. Bochkov N. P. Clinicalal genetics. The textbook. - М: GEOTAR-MED, - 2004. - 408. - 3 p
5. Atopic dermatitis. A management for doctors.//under edition Sergeyeva Y. V. medicine for all. - 2002. - 182.
6. Baranov V.S, Baranova V.E, Ivashchenko T. E., Aseev M. V. Genom of a human and "predisposition" genes: Introduction in predicative medicine. SPb.: Интермедика, - 2000. - 272.
7. Bragin E. Y. comparative analysis of structure hereditary components of susceptibility to a bronchial asthma and tuberculosis on genes of enzymes of a metabolism xenobiotics: Avtorep. dis.... Medical sciences. Tomsk, - 2005. - 23 p.
8. Vavilin V.A, Makarova S. I., Lyahovich V. V., Gavalov S. M. Association of polymorphic genes of enzymes biotransformation of xenobiotics with predisposition to a bronchial asthma at children with hereditary and without that//Genetics. - 2QQ2. - Т. 38, - No 4. - P. 539-545.
9. Gavalov S. M., Ryabov O.A, Vavilin V.A, Lyahovich V. V., Makarova S. I. Association ofpolymorphism of genes of enzymes ofbiotrans-formation and detoxication ofxenobiotics with features of a bronchial asthma in children//Allergology. - 2000. - No 3. - P. 14-21.
10. Gulyamova G. SH, Mavljanova S. Z., Boboyev K. T. role of a polymorphic variant of a gene of the factor of necrosis a tumour-alpha in development of atopic dermatitis in population of Uzbekistan.//Clinical dermatology and venereology. - No 4. - 2015. - 14. - P. 79-83.
11. Karimov H. J., Saidov A. B., Boboev K. T., Assesorova Y. Y. and others Fundamental and applied aspects of molecular genetics in medi-cine./the scientific edition. - Tashkent: ИПТД «Uzbekistan», - 2016-352 p.
12. Lyahovich V. V., Vavilin V.A, Makarova S. I., etc. Role of enzymes ofbiotransformation ксенобиотиков in predisposition to a bronchial asthma and formation of features of its clinical phenotype//the Bulletin of the Russian Academy of Medical Science. - 2000. - № 12. - S. 36-41.
13. Mavlyanova SH. Z. Atopic Dermatitis.//the Monography. - Tashkent - 2014. - 168p.
14. Abdel-Rahman S., El-Zein R. A., Anwar W. A., Au W. W. A multiplex PCR rocedure for polymorphic analysis of GSTM1 and GSTT1 genes in population studies//Cancer. Lett. - 1996. - Vol. 107. - P. 229-233.
15. Ali-Osman F., Akande O., Antoun G. et al. Molecular cloning, characterisation, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase pi gene variants//J. Biol. Chem. - 1997. - Vol. 272. - P. 10004-10012.
16. Altmuller J., Palmer L. J., Fischer G. et al. Genome wide scans of complex human diseases: true linkage is hard to find//Am. J. Hum. Genet. - 2001. - Vol. 69. - P. 936-950.
17. Altshuler D., Kruglyak L., Lander E. Genetic polymorphisms and disease//N. Engl. J. Med. - 1998. - Vol. 336: - P. 1626.
18. Blumental M. N., Nambudiri K. K., Mendell N. et al. Genetic transmission of serum IgE levels//Am.J. Med. Genet. - 1981. - Vol. 10. - P. 219-228.
19. Gambaro G., Anglani F., D'Angel A. Association studies of genetic polymorphisms and complex disease//Lancet. - 2000. - Vol. 355. -P. 308-311.
20. Hukkanen J. Xenobiotic-metabolizing cytochrome P 450 enzymes in human lung//Acta Univ. Oul. - 2000. - D 621.
21. Intestinal metabolism ofxenobiotics. In: Foster A. S. J., Richter E., Lauterbach F., HartmannF. (eds). Stuttgart: Gustav-Fischer Verlag, -1989.
22. Yang H., Yang S., Liu J. Et al. The association of GSTM1 deletion polymorphism with lung cancer risk in Chinese population: evidence from an updated meta-analysis.//Sci Rep. - 2015. - Mar 23. - 5:9392 (doi: 10.1038/srep 09392)
DOI: http://dx.doi.org/10.20534/ESR-16-11.12-52-54
Djuraev Mirjalol Dehkanovich, Egamberdiev Dilshod Makhmudovich, Djuraev Farrukh Mirjalolovich, National Cancer Research Center Ministry of Health of the Republic of Uzbekistan Tashkent Medical Academy E-mail: ndjuraev_tma@mail.ru
Choice of treatment tactics in cases of gastric cancer with liver metastases
Abstract: Currently one of the urgent problems of modern oncology is the treatment of gastric cancer with liver metastases. In this regard, the purpose of this study was to develop the optimal treatment strategy by means of evaluating different treatment approaches in gastric cancer with liver metastasis.
The study included analysis of the immediate and distant results of 74 patients with gastric cancer with liver metastases in the period from 2004 to 2016. The study included only those patients who according to investigations were diagnosed gastric cancer stage T4aN2 M1, and metastatic lesions of one or two segments of one lobe of the liver, the number of metastases 1 to 5 knots. Primary lesions of all patients were resectable, affected regional lymph nodes N2 group.
Finally, in cases of resectable gastric cancer with isolated liver metastases patients require combined surgical treatment, as only surgery increases one-year and three-year survival rates significantly, however, in the absence of possibility of surgical intervention it is recommended to conduct long term endoaortic chemotherapy, which significantly increases the average life expectancy from 8.2 to 11.3 months.
Keywords: gastric cancer, liver metastases, surgical treatment, endoaortic chemotherapy.
Gastric cancer remains one of the most common types of human malignancies. According to Axel E. M. (2012) in 2010, were diagnosed more than 1 million cases. This disease has a high mortality rate (more than 700.000 per year), making it the second cause of death in the structure of cancer mortality after lung cancer [1].
In the Republic of Uzbekistan, gastric cancer occupies the second place after breast cancer. The ratio of men to women is 2:1.
At the present time, the diagnosis and treatment of gastric cancer, as well as tumors of other organs are not unsolvable problem, but the early metastasis of gastric cancer via the lymphogenic and hematogenic ways almost complicates the problem to an unsolvable extent.
According to D. V. Podluzhny up to 87.3% (2002) metastasis in gastric cancer occurs in 80-90% of patients [6]. The most frequent localization of metastases through hematogenous via the portal system, is observed in the liver, more than 42% [3].
Currently one of the urgent problems of modern oncology is the treatment of gastric cancer with liver metastases.
Assessing the forecast, many authors identify the following factors affecting life expectancy: gender, stage of primary tumor, number of liver metastases, the distance from the resection margin
to the tumor and the stage of liver metastases [2].
Surgical treatment of liver metastases of gastric cancer still remains the preserve of a small number of surgeons, especially in view of the fact that surgery is associated with massive traumatism, the risk of complications and a high risk of fatality [5].
However, over the past 10-15 years, indications for liver resection regarding metastatic lesions has extended significantly. However, up today there are no clear indications, contra-indications to perform other method of treatment of metastatic lesion of gastric cancer. Still most of the physicians in primary general medical network and even oncologists treat patients as incurable.
Reports devoted to this subject are mostly fragmented, sparse and often controversial.
In this regard, the purpose of this study was to develop the optimal treatment strategy by means of evaluating different treatment approaches in gastric cancer with liver metastasis.
Materials and methods
The study analyzed the immediate and distant results of 74 patients with gastric cancer with liver metastases in the period from 2004 to 2016. The study included only those patients who according to investigations were diagnosed gastric cancer stage
