Metformin Caused Radiosensitivity of Breast Cancer Cells through the Expression Modulation of miR-21-5p/SESN1axis.

OBJECTIVE: In this research we evaluated molecular mechanism of effect of metformin in radio sensitivity of breast cancer cells. METHODS: This research was done in cellular and molecular research center of Qazvin university of Medical science in 1399 to 1401. Studied samples were two breast cancer cell lines (MCF-7 and MDA-MB-231) they are derived from primary and secondary tumors resected from a single patient. We exposed them to cumulative 50 Gy radiation and constructed radio resistant cell lines. Then resistant cell lines were treated with 50µm of metformin. Our studied groups were resistant cells treated and un treated with metformin. Then, the expression rate of miR-21-5p and SESN1 gene in resistant and control cells was checked by Quantitative Real-time PCR(qRTPCR). After the cell lines were treated with different concentrations of metformin at different intervals, the rate of cell proliferation and cell death was checked by CCK-8 assay and flow cytometry. The Western blot method was also used to confirm the expression of some genes. RESULTS: Our results showed that the expression of miR-21-5p was upregulated in radiation-resistant cancer cells (1.8±0.65) (P<0.0001) MCF-7 cell line and (1.6±0.42)(P<0.001) MBA-MD-231 cell line, while the expression of SESN1 was down regulated (0.46±0.12) (P<0.0001) MCF-7 cell line and (0.42±0.22) (P<0.001) MBA-MD-231 cell line. Metformin enhanced the radio sensitivity of breast cancer cells in a dose and time-dependent manner. Also, metformin treatment decreased the expression of miR-21-5p (0.47±0.32) (P<0.0001) MCF-7 Cell line and (0.45±0.21)(P<0.001) MBA-MD-231 cell line and increased the expression of SESN1 (1.65±0.72)(P<0.0001)MCF-7 cell line and (1.73±0.52)(P<0.0001) MBA-MD-231 cell line. The function of metformin was reversed by miR-21-5p inhibitors or the transfection of SESN1 overexpressing plasmids. CONCLUSION: In conclusion, based on this research results, metformin enhanced the radio sensitivity of breast cancer cells via modulating  the expression of miR-21-5p and SESN1.

Supportive care in a patient with Alstrom syndrome with hyperphenylalaninemia and sleep problems.

Alstrom syndrome is a rare genetic disorder with an autosomal recessive mutation in the ALMS1 gene. The disease's manifestations include ophthalmic problems, hearing loss, obesity, and cardiovascular disorders. In addition, medical cases include other organ complications. However, the overlapping variety of such symptoms with other diseases may delay the diagnosis. In this article, we describe the case of a 7-year-old female patient with Alstrom syndrome, and cardiovascular and hyperphenylalaninemia diseases since birth. Other symptoms included diabetes and ophthalmologic problems with skeletal disability. Blindness and hearing impairment were diagnosed, along with recurrence of respiratory problems at the age of 7 years. The patient's obesity-induced snoring predisposed her to uncontrolled blood glucose. In fact, respiratory tract problems and sleep disorders had occurred as a degraded cycle and left her with a severe disability for years. The similarity of the symptoms with other diseases had misled the physician in diagnosis. However, a polysomnography test (because of complaints of short sleep duration) recognized the source of the patient's sleep disorders and breathing problems. Eventually, we delivered a portable ventilator to the child for continuous positive airway pressure (CPAP) therapy. The child's breathing and oxygenation conditions improved. Using the ventilator and the CPAP system, we discharged her from the hospital without requiring oxygenation, in a stable condition. The procedure could prevent the patient from hypoxia and retinal problem.

Novel Homozygous Nonsense Mutation in the LRP5 Gene in Two Siblings with Osteoporosis-pseudoglioma Syndrome

Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder characterized by severe osteoporosis and eye abnormalities that lead to vision loss. In this study, clinical findings and genetic study of two siblings with OPPG are presented. Whole exome sequencing of DNA enriched for exonic regions was performed with SureSelect 38Mbp all exon kit v. 7.0. The two siblings presented with different clinical manifestations of OPPG. The younger female sibling had blindness and severe osteoporosis with multiple fractures, while her older brother was also blind but with less severe osteoporosis and no fractures. On analysis, a novel homozygous nonsense mutation (c.351G>A) in exon 2 of LRP5 (NM_002335) was found, predicted to change a tryptophan at 117 to a stop codon (p. Trp117Ter). Thus, a variable phenotype was associated with an identical variant in these two siblings. The novel mutation reported herein expands the spectrum of the underlying genetic pathology of OPPG.

Development of anti-rituximab antibodies in rituximab-treated patients: Related parameters & consequences.

The utilization of the monoclonal antibodies (mAbs) as therapeutic agents is one of the most favourable fields in immunotherapy. The immunogenicity of mAbs is one of the major parameters that may restrict their therapeutic and diagnostic applications. Rituximab, a chimeric mAb against CD20, is attached to the B-cell membrane-linked CD20 and is used to treat some B-cell-related malignancies, a number of autoantibody-mediated autoimmune disorders and improvement of graft survival. The risk of anti-rituximab antibody (ARA) development and ARA-related adverse events are low in rituximab-treated patients with lymphoma. No important association was reported between the ARA positivity and drug levels, and drug efficacy in rituximab-treated patients with lymphoma. The patients with autoimmune disorders exhibit greater risk of ARA development and ARA-related adverse events. In autoimmune diseases, ARA positivity may have no significant impact on either the drug level or its efficacy, (i.e.), it may reduce drug levels without influencing drug efficacy and, vice versa, or may reduce both drug level as well as its efficacy. The characterization of the parameters affecting the production of ARA can be used to design strategies to reduce the immunogenicity of mAb and promote its efficacy in humans. In this review, the host and therapeutic programme-related parameters affecting the development of the ARA have been discussed to suggest novel insights to reduce ARA-associated adverse events and enhance the drug efficacy.

Clinical Response to Treatment with Teriparatide in an Adolescent with Osteoporosis-Pseudoglioma Syndrome (OPPG): A Case Report.

Introduction: Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder characterized by severe osteoporosis and eye abnormalities that leads to vision loss. In this study, we report the outcome of a short period of treatment with teriparatide in one patient with OPPG. Case Presentation: The patient was a 17-year-old girl who suffered a bone fracture at the age of two and was diagnosed with OPPG at the age of three. Genetic testing was performed for the patient, and a novel homozygous nonsense mutation (c.351G>A) in exon 2 of the LRP5 gene was reported. She was treated with pamidronate, but the bone fracture increased, and the disability progressed. Therefore, at the age of 11 years and nine months, teriparatide was administered subcutaneously at a dose of 20 micrograms per day for four consecutive months. After the treatment with teriparatide, physical activity was achieved, and no further fractures were observed besides the gradual rise in bone mineral density (BMD) (from 0.532 to 0.711 gr/cm2 in lumbar spine and 0.372 to 0.635 gr/cm2 in femur neck). Conclusions: In children and adolescents diagnosed with OPPG who do not respond to other conventional therapies, short courses of teriparatide therapy may be helpful.

Thyroid Dysfunction in Children with Idiopathic Nephrotic Syndrome Attending a Paediatric Hospital in Qazvin, Iran.

OBJECTIVES: Nephrotic syndrome is a glomerular disease characterised by a loss of albumin and high-molecular-weight proteins such as thyroxine-binding globulin and thyroid hormones, potentially resulting in subclinical or even overt hypothyroidism. This study aimed to compare thyroid hormone levels between nephrotic children and healthy controls as well as between nephrotic children in the active phase of the disease and those in remission. METHODS: This case-control study was conducted between March 2016 and 2018 at a paediatric hospital in Qazvin, Iran. A total of 73 nephrotic children comprised the case group-including 49 with active disease and 24 in remission-while the control group included 74 healthy children. Thyroid function was assessed according to levels of thyroid-stimulating hormone (TSH), free triiodothyronine (T3), free thyroxine (T4), total T4, total T3 and anti-thyroid peroxidase. RESULTS: All of the controls had normal total T4 levels. Elevated TSH levels were more frequent in nephrotic children compared to controls (34.2% versus 10.8%; P = 0.001). A significantly lower number of patients with active disease were euthyroid compared to those in remission (51% versus 95.8%; P = 0.001). Moreover, 7 (9.5%) of patients in the active and no patient in remission phase had abnormal total T4 levels (P <0.001), while 14.3% and 0% had highly elevated TSH levels (P = 0.002). CONCLUSION: Due to the prevalence of subclinical and even overt hypothyroidism, thyroid screening tests may be required for nephrotic children. However, further research is needed to confirm these findings.

Identification of a novel homozygous frameshift mutation in SLC29A3 gene in a case with H syndrome from Iran.

H syndrome is a rare monogenic autosomal recessive disease with characteristic cutaneous findings and multisystem involvement. The aim of this study is to present an Iranian patient with H syndrome and to describe a novel frameshift mutation in SLC29A3 gene. The patient was diagnosed with a few small areas of hyperpigmentation and accompanying hypertrichosis in the lumbar area of her back. Her clinical phenotypes included short stature, hepatosplenomegaly, facial widespread bilateral telangiectatic lesions, bilateral hypertrophy of the parotid gland, upper extremity flexion contracture, elevated inflammatory markers (ESR, CRP) and diabetes mellitus. The identification of a novel homozygous frameshift mutation (c.307_308delTT, p.F103Ter) in SLC29A3 gene, together with the characteristic clinical manifestations of H syndrome, provided accurate diagnosis for this patient.

Efficacy of Dragon's blood cream on wound healing: A randomized, double-blind, placebo-controlled clinical trial.

The blood-red sap of Dragon's blood has been used in folk medicine for fractures, wounds, inflammation, gastrointestinal disorders, rheumatism, blood circulation dysfunctions, and cancer. Existing in vitro and in vivo bioactivity of this herb on different mechanisms of healing shows strong potential of this sap in wound healing. This clinical trial study was designated to evaluate the wound healing effect of Dragon's blood on human wounds. Sixty patients, between the ages of 14-65 years, who were referred to remove their skin tag, were assigned to this double-blind, placebo-controlled, randomized clinical trial and received either Dragon's blood or a placebo cream. They were visited on the 3rd, 5th, 7th, 10th, 14th, and 20th day of the trial to check the process of healing and to measure the wound's surface. At the end of trial, there was a significant difference in the mean duration of wound healing between the two groups (p = 0.0001). The phenolic compounds and the alkaloid taspine, which exist in Dragon's-blood resin, are probably the main reasons for the wound healing property of this plant. Being natural accessible, safe, and affordable makes Dragon's blood cream, a good choice for addition to the wound healing armamentarium. Further studies on wounds with different causes and among larger populations are suggested to ensure the effectiveness and safety of Dragon's blood.

Sleep architecture and obstructive sleep apnea in obese children with and without metabolic syndrome: a case control study.

PURPOSE: Obesity and biochemical parameters of metabolic disorders are both closely related to obstructive sleep apnea (OSA). The aim of this study was to compare sleep architecture and OSA in obese children with and without metabolic syndrome. METHODS: Forty-two children with metabolic syndrome were selected as case group and 38 children without metabolic syndrome were matched for age, sex, and BMI as control group. The standardized Persian version of bedtime problems, excessive daytime sleepiness, awakenings during the night, regularity and duration of sleep, snoring (BEARS) and Children's Sleep Habits Questionnaires were completed, and polysomnography (PSG) was performed for all study subjects. Scoring was performed using the manual of American Academy of Sleep Medicine for children. Data were analyzed using chi-square test, T test, Mann-Whitney U test, and logistic regression analysis. RESULTS: Non-rapid eye movement (NREM) sleep and N1 stage in the case group were significantly longer than the control group, while REM sleep was significantly shorter. Waking after sleep onset (WASO) was significantly different between two groups. Severe OSA was more frequent in the control group. Multivariate logistic regression analysis showed that severe OSA (OR 21.478, 95 % CI 2.160-213.600; P = 0.009) and REM sleep (OR 0.856, 95 % CI 0.737-0.994; P = 0.041) had independent association with metabolic syndrome. CONCLUSIONS: Obese children with metabolic syndrome had increased WASO, N1 sleep stage, and severe OSA. But the results regarding sleep architecture are most likely a direct result of OSA severity. More longitudinal studies are needed to confirm the association of metabolic syndrome and OSA.

Mutations of the phenylalanine hydroxylase gene in Iranian patients with phenylketonuria.

Phenylketonuria (PKU) is an autosomal recessive disease which results from mutations in the phenylalanine hydroxylase (PAH) gene. The aim of this study was the identification of sixteen different mutations in Iranian patients with hyperphenylalaninemia. The mutations were detected during the characterization of PAH genotypes of 39 PKU patients from Qazvin and Zanjan provinces of Iran. PAH mutations have been analyzed by PCR and direct sequencing of PCR products of the promoter region and all 13 exons of PAH gene, including the splicing sites. A mutation detection rate of 74.3 % was realized. Two mutations were found at high frequencies: R176X (10.25 %) and p.P281L (10.25 %). The frequencies of the other mutations were: IVS2+5G>A (2.56 %), IVS2+5G>C (2.56 %), p.L48S (2.56 %), p.R243Q (2.56 %), p.R252Q (5.12 %), p.R261Q (7.69 %), p.R261X (5.12 %), p.E280K (2.56 %), p.I283N (2.56 %), IVS9+5G>A (2.56 %), IVS9+1G>A (1.28 %), IVS11+1G>C (1.28 %), p.C357R (1.28 %), c.632delC (2.56 %). The present results confirm the high heterogeneity of the PAH locus and contribute to information about the distribution and frequency of PKU mutations in the Iranian population.

Metabolic syndrome in a sample of the 6- to 16-year-old overweight or obese pediatric population: a comparison of two definitions.

PURPOSE: The purpose of this study was to estimate the presence of metabolic syndrome (MS) in a group of children and adolescents with a body mass index (BMI) above the 85th percentile for their age and sex in Qazvin Province, Iran; to evaluate the relationship between obesity and metabolic abnormalities; and to compare two proposed definitions of MS. PATIENTS AND METHODS: The study was conducted on 100 healthy subjects aged between 6 and 16 years (average age, 10.52 ± 2.51 years) with a high BMI for their age and sex. Fifty- eight percent of subjects were female. Physical examination including evaluation of weight, height, BMI, and blood pressure measurement was performed ("overweight" was defined as a BMI between the 85th and 95th percentiles for children of the same age and sex; "obese" was defined as a BMI over the 95th percentile for children of the same age and sex). Blood levels of glucose, insulin, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and uric acid were measured after a 12-hour overnight fast. The authors used and compared two definitions of MS: the National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III) criteria and a modified definition by Weiss et al. Variables were compared using the Student's t-test and chi-square and Mann-Whitney U tests, and agreement between the two definitions was analyzed using kappa values. RESULTS: The subjects had a mean BMI of 26.02 ± 4.38 and 80% had obesity. Insulin resistance was found in 81% of the study population. MS was present in ten (50%) of the overweight and 53 (66.2%) of the obese subjects using the NCEP ATP III criteria. MS was present in five (25%) of the overweight and 34 (42.5%) of the obese subjects using the definition by Weiss et al. The overall kappa value for the two definitions of MS was 0.533. There were no statistically significant differences between the two definitions of MS in participants. CONCLUSION: The prevalence of MS in children and adolescents depends on the criteria chosen and their respective cutoff points. The NCEP ATP III criteria, the parameters of which include higher cutoff values for high-density lipoprotein cholesterol and triglycerides, detected the higher prevalence and therefore the NCEP ATP III criteria are able to diagnose a larger number of children and adolescents at metabolic risk.

Pubertal characteristics in girls of qazvin province, iran.

OBJECTIVE: Puberty is a critical time between childhood and adulthood. Many studies have reported that the mean age of breast development is decreasing. The aim of this study was to provide updated data on the pubertal development of girls and to evaluate precocious puberty in our population. METHODS: This cross sectional study was conducted in 6 to 16 year old school girls during 2009-2010 in Qazvin. 2240 healthy girls from all geographical regions with every socioeconomic status were selected by a stratified multistage cluster design to obtain representative sample of population. A questionnaire including demographic data, anthropometric measurements, secondary sexual characteristics, menarche status and its onset was filled out for every participant. Secondary sexual characteristics including breast development (B(1-5)) and pubic hair (PH(1-5)) were evaluated according to Marshal and Tanner recommendation. FINDINGS: The mean±SD of height, weight, and BMI of participants was 139.7±14.5, 36.1±12.9 and 17.9±3.7 respectively. The mean age (10th - 90th percentile) of B(2) and PH(2) were 9.71(7.67-11.4) and 9.82 years (7.84-11.42) respectively. Mean age of menstruation was 12.52 years. The mean BMI was significantly higher in pubertal females comparing to prepubertal girls (P<0.001). Average duration of puberty (the time from initiation of puberty to menarche) was 2.81 years. CONCLUSION: The mean age of pubertal onset in girls living in Qazvin is 9.71 years. Menarche occurs at mean age of 12.52 and onset of puberty earlier than 6.24 years will be precocious. We found that girls in Qazvin had a slightly earlier age of initiation of puberty and of menarche in comparison with other studies in Iran.

Etiology of precocious puberty, 10 years study in Endocrine Reserch Centre (Firouzgar), Tehran.

BACKGROUND: Precocious puberty, as early physical development and low final height might lead to psychosocial problems. OBJECTIVE: To evaluate etiology and clinical feature of precocious puberty in a cohort of Iranian children. MATERIALS AND METHODS: In this case-series study, 44 girls and 8 boys with precocious puberty referred to Endocrine Reserch Centre (Firouzgar), Institute of Endocrinology and Metabolism (Hemmat Campus), were examined in a 10 years period of time. RESULTS: Mean age of girls and boys was 7.43±1.4 years and 5.8±2.1 years respectively. Most of the patients fell within the age category of 7-7.9 years old (40.9% for girls and 50% for boys). Patients, concerning etiology of precocious puberty were classified in three categories: 42.6% of patients had central precocious puberty (CPP), including idiopathic CPP (87.5%) and neurogenic CPP (12.5%). 23.3% of patients had peripheral precocious puberty (PPP), including congenital adrenal hyperplasia (CAH) (42.8%), ovarian cysts (28.4%), McCune-Albright syndrome (14.2%) and adrenal carcinoma (14.2%). 34.1% of girls and 25% of boys had normal variant puberty including premature thelarche (57%), premature adrenarche (38%) as well as premature menarche (4.7%l). CONCLUSION: The most common etiology of precocious puberty in girls was idiopathic central precocious puberty and premature thelarche, while in boys they were neurogenic central precocious puberty and CAH. Therefore precocious puberty in girls is usually benign. In boys, CNS anomalies should first be considered in the differential diagnosis of CPP. Therefore brain Magnetic Resonance Imaging (MRI) is mandatory in all cases.

Endocrine and metabolic disorders in ß-thalassemiamajor patients.

BACKGROUND: Thalassemia is the most common hereditary anemia and beta thalassemia major is its most severe form. Endocrine abnormalities in thalassemia major are common disturbing complications that need prompt management. The purpose of this study was to determine the endocrine disorders and bone mineral density in patients with major  -thalassemia in . METHODS: In this cross- sectional study, 77 patients with - thalassemia major (15-36 years old) were enrolled. Physical examination, laboratory tests, bone radiography and bone density measurements were performed. Then, the data were analyzed. RESULTS: Forty patients were males. The mean age was 21.26±4.53 years old. The mean BMI was 20.15±2.79 kg/m(2). Impaired puberty, short stature, hypothyroidism, diabetes mellitus, IGT, hypoparathyroidism, vitamin D deficiency and vitamin D insufficiency were observed in 46.8%, 33.8%, 18.2%, 16.9%, 13%, 7.8%, 45.5% and 24.7% of patients, respectively. Nearly 80% of patients had low bone mineral density. Bone mineral density was significantly associated with hypogonadism (p=0.001), short stature (p=0.026), hypoparathyroidism (p=0.031), hypothyroidism (p=0.048), diabetes mellitus (p=0.002) and vitamin D deficiency (p<0.001). CONCLUSION: Impaired puberty and short stature were the most common endocrine complications in our population. Low bone density (osteopenia, osteoporosis) is significantly different in ß-thalassemic patients with and without endocrine complications.

Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) occurs worldwide. The most common mutations in the CYP21A2 gene in 716 unrelated patients were analyzed and the mutations were grouped by ethnicity, as defined through self-declaration corroborated by review of pedigrees extending to two or three generations. Prevalent allelic mutations and genotypes were found to vary significantly among ethnic groups, and the predominance of the prevalent mutations and genotypes in several of these populations was significant. There are ethnic-specific mutations in the CYP21A2 gene. A large deletion is prevalent in the Anglo-Saxons; a V281L (1685 G to T) mutation is prevalent in Ashkenazi Jews; an R356W (2109 G to A) mutation is prevalent in the Croatians; an IVS2 AS -13 (A/C to G) mutation is prevalent in the Iranians and Yupik-speaking Eskimos of Western Alaska; and a Q318X (1994 C to T) mutation is prevalent in East Indians. Genotype/phenotype non-correlation was seen when at least one IVS2 AS -13 (A/C to G) mutation in the CYP21A2 gene was present.