Third national surveillance of risk factors of non-communicable diseases (SuRFNCD-2007) in Iran: methods and results on prevalence of diabetes, hypertension, obesity, central obesity, and dyslipidemia

Background  

The burden of non-communicable diseases is rising globally. This trend seems to be faster in developing countries of the Middle East. In this study, we presented the latest prevalence rates of a number of important non-communicable diseases and their risk factors in the Iranian population.     

Iron status in women with and without gestational diabetes mellitus

ObjectiveGestational diabetes mellitus (GDM) affects approximately 7% of all pregnancies. Pregnancy, mostly because of the mitochondria-rich placenta, is a condition that favors oxidative stress. A transitional metal, especially iron, which is particularly abundant in the placenta, is important in the production of free radicals. Also, studies have shown that free radicals have a role in GDM. As there are little data about iron status in GDM, this study was performed to compare iron status in GDM and control group.Research Design and MethodsIn this case-control study, 34 women with diagnosed GDM were compared with 34 non-GDM women in the control group at 24–28 weeks of pregnancy in terms of iron status, including ferritin, serum iron, total iron-binding capacity (TIBC), hemoglobin (Hb), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH).ResultsIn this study, concentration of serum ferritin, iron, transferrin saturation and hemoglobin, MCV, and MCH was significantly higher in the GDM group and TIBC was significantly lower in this group (P<.05). No significant association was observed with the other variables including familial history of diabetes and GDM.ConclusionOur findings indicate an association between increased iron status and GDM. The role of iron excess from iron supplementation in the pathogenesis of GDM needs to be examined.     

Myalgia Cruris Epidemica: an unusual presentation of dengue fever

We describe a 5-year-old girl who had sudden onset difficulty in walking after 3 days of febrile illness. In the emergency department her creatine kinase level was elevated but urine myoglobin was normal. She was diagnosed as having benign acute childhood myositis. Because of poor oral intake and dehydration, she was admitted to the pediatric ward. The next day she had a petechial rash over the antecubital fossa, and dengue IgM back was positive. She was treated conservatively and recovered uneventfully. Despite dengue fever being endemic in Malaysia, this is the first case report of myositis following dengue infection in Malaysia.     

Association of CTLA-4 gene polymorphism with Graves' disease and ophthalmopathy in Iranian patients

BackgroundThe cytotoxic T lymphocyte associated antigen-4 (CTLA-4) gene, is one of the candidate genes for susceptibility to Graves' disease. This study aimed to investigate the association of Graves' disease and Graves' ophthalmopathy with polymorphisms at position + 49 in exon 1 and positions ? 318 and ? 1147 in the promoter region of CTLA-4 gene in Iranian patients.MethodsA total of 205 unrelated Iranian patients with Graves' disease who were referred to the outpatient endocrine clinic of a large university general hospital and 103 sex-matched healthy controls were included in this study. Venous blood was obtained, genomic DNA was extracted by a salting out method, and the polymorphisms at positions + 49, ? 318 and ? 1147 of the CTLA-4 gene were determined using the PCR-restriction fragment length polymorphism method (PCR-RFLP). Genotype and allele frequencies were determined.ResultsThe frequency of the G allele at position + 49 was significantly higher in patients with Graves' disease than in the control group (27.1% vs. 15.1%, OR = 2.096, 95%CI = 1.350–3.253 and p < 0.01). Significant trends were not seen for the other two polymorphisms studied. In patients with ophthalmopathy, the frequency of the G allele at position + 49 was higher than in those without ophthalmopathy (33.8% vs. 20.0%, OR = 2.043, 95%CI = 1.304–3.202 and p < 0.01).ConclusionThe results of this study suggest that the G allele at position + 49 in exon1 of the CTLA-4 gene is associated with Graves' disease and Graves' ophthalmopathy in Iranian patients.     

Delay in the administration of all-trans retinoic acid and its effects on early mortality in acute promyelocytic leukemia: Final results of a multicentric study in the United States

Early death (ED) occurs in 10–30% of patients with acute promyelocytic leukemia (APL). Is all-trans retinoic acid (ATRA) promptly given and does it decrease overall early mortality? ATRA was administered within 24 h of morphological suspicion in only 44% of the 120 consecutive patients treated in the four collaborating centers. Absence of disseminated intravascular coagulation (p = 0.012) and admission to a non-university-affiliated hospital (p = 0.032) were independent predictors of ATRA delay. ED occurred in 17% of patients, and was independently correlated only with ICU admission (p = 0.002). Our results do not demonstrate that prompt (versus delayed) ATRA administration decreases overall early death.     

Synthesis and hydrolytic behavior of ibuprofen prodrugs and their PEGylated derivatives

Polyethylene glycol (PEG) derivatives of ibuprofen were prepared by esterification of PEG monosuccinate with hydroxy ethyl ester (HEE), hydroxy ethylamide (HEA), and hydroxy ethyl thioester (HET) of ibuprofen. Hydrolysis of HEE-PEG, HEA-PEG, and HET-PEG were studied in vitro with or without esterases to investigate the applicability of these PEGylated prodrugs. The polymeric prodrugs released major fraction of the parent drug (ibuprofen) and a small fraction of hydroxy ethyl derivatives after 48 hr. In HET-PEG, the amount of drug release was higher than HEE-PEG and HEA-PEG. The difference between acidic and alkali buffered solutions was considerable. In human plasma, 50% of drug was released after 150 hr incubation at 37°C from HET-PEG.     

Progressive loss of Syk and abnormal proliferation in breast cancer cells

The tumor suppressor gene Syk tyrosine kinase is absent or reduced in invasive breast cancer tissues and cell lines; its loss in breast tissues is linked to poor prognosis and metastasis. Also, evidence shows that in vitro Syk is involved in regulating proliferation. Here, we show by in situ hybridization on breast tissue sections that the loss of Syk expression is progressive during tumor development. Strikingly, Syk is already partially lost in normal epithelial tissue adjacent to the cancer lesion. In vivo, cell proliferation (as measured by the proliferative index Ki67) increased from normal to ductal carcinoma in situ to invasive, whereas Syk in situ staining in the same tissues decreased. In vitro, the presence of Syk was associated with reduced cell proliferation in an epidermal growth factor receptor-overexpressing breast cancer cell line, BT549, whereas changes in apoptosis were undetected. Concomitantly, the kinase activity of the proto-oncogene Src was reduced by approximately 30%. A 5-fold increase in abnormal mitoses was observed in the Syk-transfected cells compared with vector control. We propose that Syk is involved in the regulation of cell proliferation, possibly by controlling mechanisms of mitosis and cytokinesis via Src signal transduction pathway(s). Because of its progressive and early loss during tumor onset and development, monitoring of Syk loss in breast epithelial cells by noninvasive techniques such as ductal lavage may be a powerful tool for screening purposes.     

Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer

Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood–brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.

Breast cancer metastasis is one of the leading causes of cancer-related deaths among women worldwide (1). This is especially true in the context of the brain, where the presence of the blood–brain barrier (BBB) significantly decreases the efficacy of the existing systemic therapies (2). The burden of brain metastatic breast cancer is further compounded by the fact that the current standard treatment is palliative and primarily local, whereby surgical resection, stereotactic radiosurgery, and/or whole-brain radiation therapy achieve limited survival benefits (3). In addition, some intracranial lesions, such as diffused multiple micrometastases or metastases close to the eloquent areas in the brain, are not suitable for surgical resection (4).The overexpression of the human epidermal growth factor receptor 2 (HER2), a tyrosine kinase receptor, is observed in about 30% of patients with breast cancer and is known to be associated with advanced disease and decreased overall survival (5). In addition, up to 50% of patients with HER2+ overexpressing breast cancer will develop central nervous system (CNS) metastases, resulting in a median survival of 11 to 18 mo after diagnosis (6–9). Trastuzumab (Herceptin), a humanized monoclonal antibody (mAb) targeting HER2, was the first clinically approved targeted therapy for the treatment of HER2+ overexpressing breast cancer and is now used routinely as the first-line therapy (10, 11). The antitumor mechanisms of trastuzumab therapy are complex, which include antibody-dependent cell-mediated cytotoxicity, inhibition of cleavage of the extracellular domain of HER2, inhibition of ligand-independent HER2 receptor dimerization, impaired activation of HER2 downstream pathways, induction of cell cycle arrest and apoptosis, inhibition of angiogenesis, and interference with DNA repair (12–14). Pertuzumab is another mAb that binds to the HER2 dimerization domain, inhibiting its heterodimerization with other HER family receptors (15, 16). In combination with trastuzumab, pertuzumab further improves invasive disease-free survival among patients with HER2+ breast cancer (17). More recently, the combination of both agents was reported to improve the response rate in patients with HER2+ metastatic breast cancer and progressive CNS metastases (18). However, the large molecular sizes of trastuzumab or pertuzumab and their weak permeability through the BBB require high dosages that can lead to toxicity. A clinical trial that evaluated the effect of tucatinib in combination with trastuzumab and capecitabine in patients with HER2+ metastatic breast cancer (HER2CLIMB) showed promising results in patients with brain metastases (19). Tucatinib (Tukysa) is a Food and Drug Administration (FDA)-approved oral tyrosine kinase inhibitor (TKI) that is highly selective for the kinase domain of HER2 with minimal inhibition of the epidermal growth factor receptor, limited low-grade toxicity, strong ability to cross the BBB, and notable antitumor activity in heavily pretreated HER2+ metastatic breast cancer patients (19–22). The risk of disease progression or death was decreased by 52% in patients with HER2+ breast cancer brain metastasis (BCBM) receiving the tucatinib combination treatment compared to those patients in the placebo combination group (23). Nevertheless, the limited efficacy of tucatinib as a monotherapy for HER2+ BCBM (24) underscores the need for innovative therapeutic regimens and delivery platforms that can improve clinical outcomes in patients with brain metastases.Human neural stem cell (NSC)-based therapies have emerged in the last few years as promising strategies for the treatment of CNS malignancies. Proof-of-concept preclinical and clinical studies have demonstrated the efficacy and feasibility of these NSCs for targeted delivery of therapeutic agents and oncolytic viruses (25–28). Our group has previously demonstrated the ability of the v-MYC immortalized HB1.F3 NSC line to deliver functional anti-HER2 antibodies (anti-HER2Ab) when injected directly in the CNS, improving significantly the survival of mice bearing breast cancer cells in the brain (4). The present study utilized the L-MYC–immortalized human NSC line LM-NSC008 (LM008), previously described as nontumorigenic in vivo and with tumor cell tropism and high migratory properties (29). Transduction of NSCs with L-MYC reduces the risk of oncogenic transformation, enhances their in vivo engraftment and migration capabilities, and results in a complete absence of tumorigenicity for up to 9 mo when injected in mouse brains (30, 31). After modifying the LM008 cells to secrete stable and high amounts of anti-HER2Ab (LM008–HER2Ab cells), we analyzed their efficacy when delivered locally in the brain and systemically in a model of multiple HER2+ BCBM. Our results demonstrate a significant survival benefit in mice injected with LM008–HER2Ab cells that was further improved when these mAb-secreting NSCs were used in combination with tucatinib. Thus, this study provides compelling evidence for the use of LM008–HER2Ab NSCs in combination with tucatinib for the treatment of HER2+ overexpressing BCBM.