Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 21, Issue 3, 2021

Background: According to the American Cancer Society, prostate cancer ranks second in terms of mortality and is a front-runner of newly detected cases. Conventional therapies neither eradicated cancer nor increased the life expectancy of patients obviating the need for less toxic as well as efficient therapies to treat cancer. Gene therapy alone, or in combination with conventional therapies, possesses a strong potential to combat cancer. Methods: This review encompasses a brief note on the etiology and conventional therapy of prostate cancer with an emphasis on gene therapy and its suitability for the treatment of prostate cancer. Results: A comprehensive range of gene therapy approaches have been successfully explored for prostate cancer treatment in animal models and this has been well translated into early clinical trials. We have also discussed in brief about specific therapeutic genes and suitable vector systems for gene therapy in prostate cancer. Conclusion: Based on the results of these clinical trials, the application of gene therapy in prostate cancer therapeutics can be satisfactorily established.

Background and objective: Immune thrombocytopenia (ITP) is a common bleeding disorder in childhood. The management of ITP in children is controversial, requiring personalized assessment of patients and therapeutic choices. Thrombopoietin receptor agonists (TPO-RAs), eltrombopag and romiplostim, have been shown to be safe and effective for the treatment of pediatric ITP. The aim of our research is to define the role of thrombopoietin receptor agonists in the management of pediatric ITP. Methods: This review focuses on the use of TPO-RAs in pediatric ITP, in randomized trials and in clinical routine, highlighting their key role in the management of the disease. Results: Eltrombopag and romiplostim appear effective treatment options for children with ITP. Several clinical studies have assessed that the use of TPO-RAs increases platelet count, decreases bleeding symptoms and improves health-related quality of life. Moreover, TPO-RAs are well tolerated with minor side effects. Conclusion: Although long term efficacy and safety of TPO-RAs still require further investigations, their use is gradually expanding in the clinical practice of children with ITP.

Background: Cannabis sativa L. (C. sativa) is a plant whose use as a therapeutic agent shares its origins with the first Far East’s human societies. Cannabis has been used not only for recreational purposes but as food to obtain textile fibers, to produce hemp paper, to treat many physical and mental disorders. Aim: This review aims to provide a complete assessment of the deep knowledge of the cannabis psychoactive effects and medicinal properties in the course of history covering i.) The empirical use of the seeds and the inflorescences to treat many physical ailments by the ancient Oriental physicians’ ii.) The current use of cannabis as a therapeutic agent after the discovery of its key psychoactive constituent and the human endogenous endocannabinoid system. Methods: This study was performed through a detailed analysis of the studies on the historical significance and medical applications of Cannabis sativa by using international scientific databases, historical and medical books, ancient Greek and Chinese manuscripts translations, library and statistical data from government reports and texts from the National Library of Greece (Stavros Niarchos Foundation), from the School of Health Sciences of the National and Kapodistrian University of Athens (Greece). We selected papers and texts focusing on a historical point of view about the medical importance of the plant and its applications for a therapeutic purpose in the past. Results and Conclusion: Through a detailed analysis of the available resources about the origins of C. sativa, we found that its use by ancient civilizations as a source of food and textile fibers dates back over 10,000 years, while its therapeutic applications have been improved over the centuries, from the ancient East medicine of the 2nd and 1st millennium B.C. to the more recent introduction in the Western world after the 1st century A.D. In the 20th and 21st centuries, Cannabis and its derivatives have been considered as a menace and banned throughout the world, but nowadays, they are still the most widely consumed illicit drugs all over the world. Its legalization in some jurisdictions has been accompanied by new lines of research to investigate its possible applications for medical and therapeutic purposes.

Background and Objective: Psoriasis is an autoimmune skin disease involving cascading release of cytokines activated by the innate and acquired immune system. The increasing prevalence rate of psoriasis demands for more appropriate therapy. The existing chemical moiety is promising for better therapeutic outcome, but the selection of a proper channel for administration has to be reviewed. Hence there is a need to select the most appropriate dosage form and route of administration for improving the curative rate of psoriasis. Results: A total of 108 systematic reviews of research and review articles were conducted to make the manuscript comprehensible. The role of inflammatory mediators in the pathogenesis of the disease is discussed for a better understanding of the selection of pharmacotherapy. The older and newer therapeutic moiety with its mode of administration for psoriasis treatment has been discussed. With a comparative review on topical and oral administration of first-line drugs such as methotrexate (MTX), cyclosporine (CsA), and betamethasone, its benefits-liabilities in the selected routes were accounted for. Emphasis has also been paid on advanced nanocarriers for dermatologic applications. Conclusion: For a better therapeutic outcome, proper selection of drug moiety with its appropriate administration is the major requisite. With the advent of nanotechnology, the development of nanocarrier for dermatologic application has been successfully demonstrated in positioning the systemically administrated drug into topical targeted delivery. In a nutshell, to achieve successful treatment strategies towards psoriasis, there is a need to focus on the development of stable, non-toxic nanocarrier for topical delivery. Inclusion of the existing orally administered drug moiety into nanocarriers for topical delivery is proposed in order to enhance therapeutics payload with reduced side effects which serves as a better treatment approach for relief of the psoriasis condition.

Background: Matthiola maroccana (Coss.) belongs to the Brassicaceae family and it is an endemic plant from Morocco. Objective: The objective of the study was to evaluate the effect of aqueous extract of Matthiola maroccana (Coss.) on blood glucose levels in normal and diabetic rats. Methods: The effect of single dose (6 hours) and daily oral administration for seven days of the Aerial Part Aqueous Extract (A.P.A.E) of Matthiola maroccana (Coss.) (M. maroccana) at a dose of 20 mg/kg body weight on blood glucose levels in normal and streptozotocin(STZ)-induced diabetic rats was observed. Furthermore, body weight, oral glucose tolerance test, liver histopathological examination, phytochemical screening, and in vitro antioxidant activity of A.P.A.E were evaluated in this study. Results: The results showed that M. maroccana A.P.A.E exerts potent hypoglycemic and antihyperglycemic effects on normal and STZ-induced diabetic rats (p<0.0001). Also, it was able to restore body weight in diabetic rats (p<0.05). Furthermore, the aqueous extract has been shown to regenerate hepatic tissues in diabetic rats. Besides, A.P.A.E revealed the presence of several phytochemical constituents (polyphenols, flavonoids, tannins, saponins, alkaloids, sterols and terpenoids), and possessed antioxidant activity. Conclusion: In conclusion, our findings showed that A.P.A.E of M. maroccana (A.P.A.E MM) possesses significant antihyperglycemic and hypoglycemic activities.

Objective: Glucose metabolism increases ATP/ADP ratio within the β-cells and causes ATP-sensitive K+ (KATP) channel closure and consequently insulin secretion. The enhanced activity of the channel may be a mechanism contributing to the reduced first-phase of insulin secretion observed in T2DM. There is no study to date in the Kurdish ethnic group regarding the relationship between SNP Ala1369Ser (rs757110 T/G) of SUR1 gene and T2DM, and additionally, the results of this association in other populations are inconsistent. Therefore, our aim in this study was to explore the possible association between SNP Ala1369Ser and type 2 diabetes in an Iranian Kurdish ethnic group. Methods: In this study, we checked out the frequency of alleles and genotypes of SNP Ala1369Ser in T2DM individuals (207 patients; men/women: 106/101) and non-T2DM subjects (201 controls; men/women: 97/104), and their effects on anthropometric, clinical, and biochemical parameters. Genomic DNA was extracted from the leukocytes of blood specimens using a standard method. We amplified the ABCC8 rs757110 polymorphic site (T/G) using a polymerase chain reaction (PCR) method and a designed primer pair. To perform the PCR-RFLP method, the amplicons were subjected to restriction enzymes and the resulting fragments separated by gel electrophoresis. Results: The frequency of the G-allele of Ala1369Ser polymorphism was significantly (0.01) higher in the case group than the control group (19% vs. 9%, respectively). In the dominant model (TT vs. TG+GG), there was a significant relationship between this SNP and an increased risk of T2DM (P = 0.00). T2DM patients with TG+GG genotypes had significantly higher fasting plasma insulin and HOMA-IR than those who had the TT genotype (P = 0.02 and 0.01, respectively). Conclusion: Our study is the first study to investigate the association between Ala1369Ser ABCC8 genetic variation and T2DM in the Kurdish population of western Iran. The obtained results clearly show that Ala1369Ser polymorphism of ABCC8 is associated with an increased risk of T2DM in this population.

Aims: The aim of this study was to investigate the epidemiology of histology-proven Neuroendocrine neoplasms (NENs) in an Italian area. Background: NENs are a rare and poorly known disease and the global incidence and prevalence appear to be increasing over the past decades. Objective: The objectives of this study were to estimate the incidence and trends of NENs in a 250,000-inhabitant area in the North-East of Italy in the 1998-2018 period and to compare them with international data. Methods: This retrospective cohort study was based on the analysis of anonymous health administrative databases, linked with each other at individual patient level through an anonymous stochastic key. NENs were identified from the anatomical pathology database. The standardized incidence rate (2010ESP and US2000) ± 95% CI per 100,000 were calculated, both annually and globally, for the whole period. Incidence was also calculated for specific anatomical sites and by gender. Trends for the considered periods and sites were summarized through the annual percent change (APC) and average increase (cases per 100,000 per year). Results: In the 1998-2018 period, the standardized incidence rate of NENs in the area of Udine was 2.49 (APC 3.33). A total of 162 cases were observed (51.2% males). Differences in incidence and trend were observed between sexes. The obtained results were consistent with those reported in other countries, confirming a significant and steady increase in NENs incidence in the last twenty years. Conclusion: This study provides new epidemiological data on NENs in Italy. The observed sex differences deserve further investigations.

Background: Cisplatin is a chemotherapeutic drug used to treat testicular cancer that induces testicular toxicity. This study aimed to investigate the possible role of androgens, androgen receptor, and organic cation transporter 2 (OCT2) in the protective effects of curcumin on cisplatininduced testicular toxicity. Methods: Thirty male Wistar rats were divided into five groups: 1- control (normal saline, 0.5 ml ip, daily for 10 consecutive days); 2- cisplatin (10 mg/kg ip, single dose at the first day); 3- cisplatin + curcumin (10 mg/kg ip, dissolved in 5% DMSO, daily for 10 consecutive days); 4- cisplatin + vehicle (DMSO 5%, 0.3 ml ip); and 5- curcumin (10 mg/kg ip). At the end of the study, a blood sample was obtained for testosterone measurement. The left testis was kept at -80 to measure androgen receptor (AR) and type 2 organic cation transporter (OCT2) gene expression and the right testis were kept in 10% formalin for histological analysis. Results: Cisplatin significantly decreased serum testosterone, declined testis AR gene expression, and increased OCT2 gene expression in testis (p<0.01). Curcumin treatment significantly prevented these alterations in testosterone and gene expressions (p<0.01). Moreover, curcumin significantly reversed the cisplatin-induced kidney tissue injury and increased spermatid and spermatozoa. Conclusion: It is concluded that the ameliorative effect of curcumin in cisplatin-induced reproductive disorders was due to the modulation of testosterone and androgen receptors.

Background: Diabetes prevalence at Palestine was 10%, with a rising fund crisis, and diabetes healthcare problems. There was a limited research concerning diabetes healthcare dimensions including organizational factors and their predictors. Objective: This study described patient characteristics and organizational factors, and assessed relationships among organizational factors of type 2 diabetes health care in Palestine. Methods: This study is a retrospective cross sectional study, recruited by convenience sampling method in 330 participants from a type 2 diabetes patients list. It was carried out at Ramallah, Palestine. The Statistical Package for Social Sciences (SPSS v 19) was used to analyze data on patient characteristics and organizational factors collected from personal interview and medical records review. Results: The results showed that 51.2% were males, and 88.5% had additional chronic diseases. Preventive healthcare and patient–healthcare professionals’ relationship were the most prominent organizational factors in statistically significant relationships among organizational factors. Conclusion: This study reflected the need for reviewing prescription mode, and educational programs that emphasize the diabetes self–care management and the health care providers’ role that would be of great benefit in health outcomes further.

Background: Gasdermin A (GSDMA) and Gasdermin B (GSDMB) have been associated with childhood and to a lesser extent with adult asthma in many populations. In this study, we investigate whether there is an association between GSDMA (rs7212938, T/G) and GSDMB (rs7216389, T/C) at locus 17q21.2 and risk of Allergic Rhinitis among Jordanians. Also, we aimed to determine if there is an association between such polymorphisms and the IgE level. Methods: The study included 112 rhinitis patients and 111 Healthy controls. Gasdermin A (GSDMA) (rs7212938, T/G) and Gasdermin B (rs7216389, T/C) polymorphisms were genotyped using the PCRRFLP method. Results: On the genotype level, three analysis models were applied namely co-dominant, dominant and recessive genotypes. GSDMB CC genotype was found to have a significant protective effect against allergic Rhinitis (< 0.05). cc genotype was also significantly associated with higher IgE level among the studied population. Conclusion: The GSDMB CC of homozygous minor genotype showed a protective effect against Allergic rhinitis. It also was found to be significantly associated with lower IgE level among the studied population. No association was found between GSDMA with the risk of allergic Rhinitis.

Introduction: Obesity is a disorder with low-grade chronic inflammation that plays a key role in hepatic inflammation and steatosis. Moreover, there are studies to support the role of exosomes in cellular communications, the regulation of metabolic homeostasis and immunomodulatory activity. Accordingly, we aimed to evaluate the influence of plasma circulating exosomes derived from females with normal-weight and obesity on the secretion of inflammatory cytokines in human liver cells. Methods: Plasma circulating exosomes were isolated from four normal (N-Exo) and four obese (OExo) women. The exosomes were characterized and approved for CD63 expression (common exosomal protein marker) and morphology/size using the western blot and TEM methods, respectively. The exosomes were used for the stimulation of HepG2 cells in vitro. After 24 h of incubation, the protein levels of TNF-α, IL-6, and IL-1β were measured in the culture supernatant of HepG2 cells using the ELISA kit. Results: The protein levels of IL-6 and TNF-α in the cells treated with O-Exo and N-Exo reduced significantly in comparison with the control group (P=0.039 and P<0.001 respectively), while significant differences were not found between normal and obese groups (P=0.808, and P=0.978 respectively). However, no significant differences were found among the three groups in terms of IL-1β levels (P=0.069). Based on the correlation analysis, the protein levels of IL-6 were positively correlated with TNF-α (r 0.978, P<0.001). Conclusion: These findings suggest that plasma circulating exosomes have probably antiinflammatory properties independent of body mass index and may decrease the secretion of inflammatory cytokines in the liver. However, further in vitro and in vivo investigations are needed to address the anti-inflammatory function of N-Exo and O-Exo in human liver cells and/or other cells.

Background: We hypothesized that the SKA2 gene can convert hemoglobin F to A leading to the maturity of the hematopoietic system by glucocorticoid hormone; so, the present study aimed to investigate the health outcome of newborns by using the effect of SKA2 gene on hematopoietic maturation. Methods: At first, 142 samples were divided into term and preterm. After sampling from the umbilical cord blood, the expression of SKA2 genes and HbA and F were evaluated by quantitative RT-PCR. The blood gases were measured by Campact 3 device. Finally, the cortisol level was measured by ELISA method and HbA and F levels were investigated by capillary electrophoresis. Results: The blood gases and Apgar scores were more favorable in term newborns (P <0.001). Levels of protein/expression of HbF in newborns with Apgar score greater than 7 was lower than that of the newborns with Apgar score below 7 (P <0.001). Cortisol and HbA levels were considerably higher in term newborns compared to the preterm ones (P <0.001). In the preterm and term groups, SKA2 gene expression had a positive and significant relationship with cortisol and HbA levels as well as a negative relationship with the HbF level. In the preterm group, a positive and significant relationship was observed between the expression of SKA2 and HbF genes. Conclusion: The results revealed that the SKA2 gene affected hematopoietic maturation in preterm and term newborns and the health outcome of newborns improved by increasing HbA level.

Background: Diabetes increases the risk of myocardial infarction (MI) by 2 to 3 folds. Tlymphocytes play a role in atherosclerosis, which is the main pathology behind MI. Cellular immune responses to beta-2 glycoprotein I (β2GPI) are shown in carotid atherosclerosis. Objective: To investigate the self-reactive, β2GPI-specific T-lymphocytes in patients with and without diabetes and atherosclerosis. Methods: Collectively, 164 subjects with and without diabetes that underwent coronary angiography were divided into four groups based on their diabetes status and coronary stenosis. Group I=Diabetic with ≥50% stenosis: A+D+ (n=66); Group II=Non-diabetic with ≥50% stenosis, A+D- (n=39); Group III=Diabetic with <50% stenosis: A-D+ (n=28); and Group IV=Non-diabetic with <50% stenosis: AD- (n=31). All groups were evaluated for anti-β2GPI IgG antibody by ELISA method. Then, PBMCs were isolated from 18 subjects and were stimulated with β2GPI-derived peptides to assess their proliferation in accordance with their HLA-DRB1 alleles. Results: Mean β2GPI IgG levels were higher in groups with ≥50% stenosis (A+) compared to those with <50% stenosis (A-), (P=0.02). The co-presence of diabetes in A+ individuals increased mean β2GPI-specific IgG. Auto-reactive β2GPI-specific T cells were detected in the repertoire of T-lymphocytes in all groups. β2GPI-peptides showed promiscuous restriction by various HLADRB1. Conclusion: β2GPI is the target of cellular and humoral immune responses in patients with atherosclerosis. Since the T cell responses but not antibodies were detectable in A-D+ and A-D- groups, it is reasonable to assume that cellular responses preceded the humoral responses. Post-translation modifications of β2GPI under oxidative and glycemic stresses may have increased the IgG levels in patients with diabetes. Finally, identification of antigens that trigger immuno-pathogenesis in atherosclerosis and diabetes may help the development of immunomodulation methods to prevent or treat these debilitating diseases.

Background: sRAGE (soluble receptor for advanced glycation end products) is known to play a protective role in chronic inflammatory diseases, and has been found to be related to arterial stiffness in hypertensive or diabetic patients. This cross-sectional study was designed to study the potential association of sRAGE with arterial stiffness in systemic lupus erythematosus(SLE) patients. Methods: A total of 94 female SLE patients were enrolled. Brachial-ankle pulse wave velocity (baPWV) was measured by an automatic pulse wave analyzer. The patients were divided into two groups according to the baPWV values, those with values greater than 1400cm/s were placed in the high arterial stiffness group. Biochemical parameters were compared between the two groups. Linear and logistic regression analysis was used to observe the association between sRAGE and arterial stiffness in these patients. Results: Thirty-five patients were placed in the high arterial stiffness group in which sRAGE levels were lower (P<0.05). sRAGE levels were significantly related to baPWV(standardized β=1.18, P<0.01) by linear regression analysis. Multivariate logistic regression analysis showed that sRAGE, SLE duration, systolic blood pressure, and low-density lipoprotein cholesterol were independent predictors of arterial stiffness in these patients. Conclusion: The results revealed that sRAGE was negatively associated with arterial stiffness in Chinese female SLE patients.

Background: Hypoxia (deprived oxygen in tissues) may induce molecular and genetic changes in cancer cells. Objective: To Investigate the genetic changes of glucose metabolism in breast cancer cell line (MCF7) after exposure to continuous hypoxia (10 and 20 cycles exposure of 72 hours continuously on a weekly basis). Methods: Gene expression of MCF7 cells was evaluated using real-time polymerase chain reactionarray method. Furthermore, cell migration and wound healing assays were also applied. Results: It was found that 10 episodes of continuous hypoxia activated the Warburg effect in MCF7 cells, via the significant up-regulation of genes involved in glycolysis (ANOVA, p value < 0.05). The molecular changes were associated with the ability of MCF7 cells to divide and migrate. Interestingly, after 20 episodes of continuous hypoxia, the expression glycolysis mediated genes dropped significantly (from 30 to 9 folds). This could be attributed to the adaptive ability of cancer cells. Conclusion: It is concluded that 10 hypoxic episodes increased the survival rate and aggressiveness of MCF7 cells and induced the Warburg effect by the up-regulation of the glycolysis mediating gene expression.

Background: Cytokines are polypeptides that play critical roles in immune responses. Gene polymorphisms occurring in the inflammatory cytokines are taking a role in autoimmune diseases, including multiple sclerosis (MS), which may induce inappropriate immune responses. Objective: The aim of this study was to investigate the allelic and genotypic frequencies of interferon gamma gene (IFN-γ) at +874A/T locus and tumor necrosis factor (TNF-α) at+308A/G locus in MS patients of Azeri population. Methods: At first, a questionnaire was prepared for each of 240 healthy, non-relative, and 152 Azeri MS patients before obtaining the blood sample from all subjects. After DNA extraction, the frequency of alleles and genotypes of the IFN-γ and TNF-α genes at +874A/T and -308G/A loci, respectively, were determined by allele-specific PCR method. Finally, the frequencies were compared between control and MS patients by chi-square test (x²-test) and p<0.05 was considered significant. Results: In the IFN-γ +874A/T gene single nucleotide polymorphism (SNP), the most allelic and genotypic frequencies in MS patients were the A allele, 55.26% (p=0.04) and the AT genotype, 52.63% (p=0.048). In healthy individuals, it was 65.42% for the A allele and 45.42% for the AA genotype. For the TNF-α 308 G/A SNP, the highest allelic and genotypic frequencies in MS patients were the G allele with 55.92% (p<0.001) and AG genotype with 61.84%, and in healthy subjects, the allelic and genotypic frequencies were 84.2% and 70.8% for the G allele and GG genotype, respectively. Conclusion: Head trauma, the infection with the herpes virus and Mycoplasma pneumonia, frequent colds and high consumption of canned foods provide grounds for MS. The T allele in the IFN-γ gene (+874) and the genotypes of AA and AG at the TNF-α gene (-308) at the position-308 were considered as potential risk factors for MS. Therefore, the polymorphisms in cytokine genes and following changes in their expression levels can be effective in susceptibility to MS.

Background and Objective: All three isoforms of nitric oxide (NO) synthase (NOS) are targets for thyroid hormones in the cardiovascular system. The aim of this study was to assess the effects of hypo- and hyperthyroidism on inducible (iNOS), endothelial (eNOS), and neural (nNOS) NOS levels in aorta and heart tissues of male rats. Methods: Rats were divided into control, hypothyroid, and hyperthyroid groups; hypo- and hyperthyroidism were induced by adding propylthiouracil (500 mg/L) and L-thyroxine (12 mg/L) to drinking water for a period of 21 days. On day 21, systolic blood pressure, heart rate, left ventricular developed pressure (LVDP), peak rate of positive and negative (±dp/dt) changes in left ventricular pressure as well as NO metabolites (NOx) and iNOS, eNOS, and nNOS protein levels in aorta and heart, were all measured. Results: Compared to controls, LVDP and ±dp/dt were lower in both hypo- and hyperthyroid rats. Compared to controls, heart rate and systolic blood pressure were lower in hypothyroid and higher in hyperthyroid rats. NOx levels in the heart of hypothyroid rats were lower (53%), whereas that in hyperthyroid rats were higher (56% and 40%) than controls. Compared to controls, hypothyroid rats had lower levels of eNOS, iNOS, and nNOS in the aorta (16%, 34%, and 15%, respectively) and lower iNOS and higher nNOS in heart tissue (27% and 46%). In hyperthyroid rats, eNOS levels were lower (54% and 30%) and iNOS were higher (63%, and 35%) in the aorta and heart while nNOS was lower in the aorta (18%). Conclusion: Hypothyroidism increased while hyperthyroidism decreased the ratio of eNOS/iNOS in aorta and heart; these changes of NOS levels were associated with impaired cardiovascular function.

Background: Multiple endocrine neoplasia type 2B (MEN 2B) is mainly caused by M918T RET germline mutation, and characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO) and non-endocrine features. However, the diagnosis and treatment are usually delayed. Methods: This study reports 5 Chinese pedigrees with 5 individuals harboring germline RETM918T, and systematically reviewed previous Chinese literature reported. Results: All 5 patients initially presented MTC, but none had biochemically cured postoperatively. 2 also presented bilateral PHEO after adrenal-sparing surgery, 1 needed steroid replacement. Further, a total of 32 MEN 2B patients from literature were clustered with 28 available for analysis. 26 (92.8%) were diagnosed by endocrine-related symptoms; the remaining 2 (7.2%) due to RET testing and oral symptoms, respectively. 25 patients underwent thyroidectomy with/without neck lymph node dissection at the mean age of (23.3 ± 10.4) years. Histopathological examination revealed MTC (100%). Of them, 17 had definite TNM stage, with 1 in stage III and others in IV. Other information of MEN 2B-related symptoms included penetrance of PHEO (60.7%), constipation (32.1%), Hirschsprung disease (25%), alacrima (17.8%), mucosal ganglioneuroma (96.4%) and marfanoid habitus (71.4%). 19 patients were verified harboring RET-M918T (c.2753T>C), of whom 15 (78.9%) were de novo mutation. The other 9 were clinically diagnosed as MEN 2B. Discussion & Conclusion: The initial diagnosis of MEN 2B is relatively later, and diagnosed by non-endocrine components is extremely lower. Recognition of MEN 2B and its non-endocrine-related components is still the utmost requirement for a Chinese physician. Combined RET screening and serum calcitonin detection can facilitate early diagnosis.

Aim: Hypoxia-inducible factor 1 (HIF-1α) is responsible in regulating oxygen homeostasis in tissues and is a central effector of the hypoxic response besides its protein overexpression has been shown to have prognostic relevance in several cancers including breast cancer. Several reports indicated that HIF-1α gene variation C1772T (Pro582Ser) is associated with increased breast susceptibility but results remained controversial. Therefore, we performed the molecular evaluation of HIF-1α gene variation and determined its frequency and association with Breast Cancer susceptibility in Saudi Arabia. Methods: This study was conducted on histologically confirmed Breast cancer patients and gender matched healthy women. HIF-1α C1772T (Pro582Ser) genotyping was done by Amplification refractory mutation system PCR method. The HIF-1α gene genotypes were correlated with different clinicopathological characteristics of breast cancer patients. Results: A significant difference was observed in genotype distribution of HIF-1α gene variation C1772T (Pro582Ser) between breast cancer cases and gender matched healthy controls (P=0.010). Our findings showed that the HIF- 1α variant was associated with an increased risk of Breast cancer for HIF-1α CC vs CT genotype OR = 2.20, 95% CI = (1.28 -3.77), P = 0.004) in codominant inheritance model. The significant association was reported for HIF1A for genotypes CC vs (CT+ TT) OR = 1.98, 95% CI = (1.17-3.34), P = 0.010) in dominant inheritance model tested. In case of recessive inheritance model, a non-significant association of HIF-1 alpha gene variants was reported for (CC+ CT) vs TT) OR = 1.03, 95% CI = (0. 064-16.79), P = 0.97). During the allelic comparison, a non-significant association was reported between A vs C allele among Breast cancer patients. A significant association of HIF- 1α polymorphism was reported with stage as well as distant metastasis of the disease. Conclusion: A significant difference was observed in genotype distribution of HIF-1α gene variation C1772T (Pro>Ser) between breast cancer cases and gene matched healthy controls (P=0.010). HIF-1α- CT heterozygosity and CC genotype increased the susceptibility .The HIF-1α polymorphism was reported to be significantly associated with the distant metastasis of Breast cancer. Further studies with larger data set and well-designed models are required to validate our findings.

Background: Mixed medullary and follicular thyroid carcinoma (MMFC) displays heterogeneous morphological components and immunophenotypical features intermingled within the same lesion, which is rare and most described in the sporadic form. We report herein a Chinese patient with multiple endocrine neoplasia type 2B (MEN2B) harboring germline RET M918T and associated MMFC. Methods: A case of a 39-year-old male patient with MEN2B presented palpable neck masses in both thyroid lobes (maximum sizes: left, 3.9 cm; right, 5.4 cm) and a definitive phenotype. Serum levels of calcitonin (Ctn; >2000pg/mL), carcinoembryonic antigen (CEA; 719.27ng/mL), and thyroglobulin (Tg; 98.54ng/mL) were high. Fine-needle aspiration cytology showed features positive for malignancy, suggesting the possibility of medullary thyroid carcinoma (MTC). Total thyroidectomy, along with extending bilateral neck lymph nodes dissection, and subsequently, genetics family screening were performed. Results: The histopathological examination yielded a diagnosis of MMFC that showed immunohistochemical characteristic patterns of the component of MTC positive for Ctn and CEA, chromogranin A, and the follicular carcinoma components were positive for Tg. Lymph node metastasis was observed showing medullary tumoral cells positive for Ctn and follicular-like structures lacking tumor cells positive for Tg staining (T4bN1bM0). Genetics screening confirmed RET M918T (c.2753T>C) mutation manifested in the patient but was not detected in other family members. Follow up showed that the serum Ctn, CEA and Tg levels respectively dropped to 54.38pg/ml, 4.16ng/mL and 0.04ng/mL 16 months after the surgery. Conclusion: Particular and diverse patterns of MMFC should be recognized with immunostaining features. MMFC occurring in a patient with MEN2B harboring RET M918T may be unique biological behavior and the treatment is mostly radical surgery.