Transplanted human photoreceptors transfer cytoplasmic material but not to the recipient mouse retina.

BACKGROUND: The discovery of material transfer between transplanted and host mouse photoreceptors has expanded the possibilities for utilizing transplanted photoreceptors as potential vehicles for delivering therapeutic cargo. However, previous research has not directly explored the capacity for human photoreceptors to engage in material transfer, as human photoreceptor transplantation has primarily been investigated in rodent models of late-stage retinal disease, which lack host photoreceptors. METHODS: In this study, we transplanted human stem-cell derived photoreceptors purified from human retinal organoids at different ontological ages (weeks 10, 14, or 20) into mouse models with intact photoreceptors and assessed transfer of human proteins and organelles to mouse photoreceptors. RESULTS: Unexpectedly, regardless of donor age or mouse recipient background, human photoreceptors did not transfer material in the mouse retina, though a rare subset of donor cells (< 5%) integrated into the mouse photoreceptor cell layer. To investigate the possibility that a species barrier impeded transfer, we used a flow cytometric assay to examine material transfer in vitro. Interestingly, dissociated human photoreceptors transferred fluorescent protein with each other in vitro, yet no transfer was detected in co-cultures of human and mouse photoreceptors, suggesting that material transfer is species specific. CONCLUSIONS: While xenograft models are not a tractable system to study material transfer of human photoreceptors, these findings demonstrate that human retinal organoid-derived photoreceptors are competent donors for material transfer and thus may be useful to treat retinal degenerative disease.

Physical activity level (PAL) and risk factors of cardiovascular disease in the MASHAD study cohort.

BACKGROUND AND AIM: The relationship between physical activity levels (PAL) and the presence of cardiovascular disease (CVD) risk factors such as anthropometric and biochemical indices and heat shock proteins 27 antibody (anti-HSP-27) concentration, and serum inflammatory markers, was investigated in the MASHAD cohort study. METHODS: The overall study population consisted of 9,684 subjects (3,858 men, 5,826 women) with a mean age of 47.73 ± 8.08 to 48.87 ± 9.26 years respectively. They were divided into four categories based on their PAL. Biochemical parameters were determined for all participants. Also, serum anti-HSP-27 levels were measured using an in-house enzyme-linked immune sorbent assay method. Multiple regression analysis was used to explore the association between the anti-HSP antibody titers and physical activity after adjusting for confounding factors. The level of statistical significance was set at p < 0.05. RESULTS: Several CVD risk factors were associated with the level of PAL including: body mass index, waist hip ratio, systolic and diastolic blood pressure, serum HDL-C and TG (p < 0.001) and also fasting blood glucose (0.004). Also, serum anti-HSP-27 titers were significantly higher in inactive subjects (P > 0.05). CONCLUSION: We found that PAL was significantly associated with several established CVD risk factors. Also, the level of anti-HSP-27 was lower in individuals with moderate and high PAL.

Single Nucleotide Polymorphisms as the Efficient Prognostic Markers in Breast Cancer.

BACKGROUND: Breast cancer (BC) is known as the most common malignancy in women. Environmental and genetic factors are associated with BC progression. Genetic polymorphisms have been reported as important risk factors for BC prognosis and drug response. Main Body: In the present review, we have summarized all of the single nucleotide polymorphisms (SNPs) which have been significantly associated with drug response in BC patients in the world. We have also categorized the reported SNPs based on their related gene functions to clarify the molecular biology of drug responses in BC. CONCLUSION: The majority of SNPs were reported in detoxifying enzymes which introduced such genes as the main genetic risk factors during BC drug responses. This review paves the way for introducing a prognostic panel of SNPs for the BC patients in the world.

Association of a variant in the tumor necrosis factor alpha gene with risk of cervical cancer.

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine involved in the regulation of the immune system and potentially the progression of cervical neoplastic lesions. In this study, we aimed to explore the possible relationship between polymorphisms of the TNF-α gene and susceptibility to cervical cancer. The relationship between a single nucleotide polymorphism (SNP) in the TNF-α gene (rs1800629) and the risk of cervical cancer was evaluated in a total of 445 subjects with (n = 153), or without (n = 292) cancer. Genotyping was performed using a Taq-Man based real time PCR method. Logistic regression analysis showed that individuals with AG/AA genotypes had an increased risk of cervical cancer compared to those with a GG genotype (OR 3.79, 95% CI 2.4-5.7, < 0.001). Our findings demonstrated that a genetic variant in the TNF-α gene (rs1800629) was associated with increased level and risk of developing cervical cancer, suggesting its potential use as a genetic risk factor for cervical neoplasia.

The association between genetic variants in the genes for cytochrome P450 B1 and ATP-binding cassette transporter genes and breast cancer risk.

Breast cancer is among the most common malignancies in women. Recent studies have shown that polymorphisms in genes involved in the metabolism and transport of anticancer drugs are associated with outcomes of several malignancies, e.g., breast cancer. In this study we evaluate whether CYP1B1/rs1056836 and ABCB1/rs2032582 gene variants are associated with breast cancer. Eighty eight cases and 200 controls, were genotyped for polymorphisms of the CYP1B1 and ABCB1 genes using Taqman®-based methods. Logistic regression was also used to test the associations between breast cancer risk and the various genotypes involved. The GG genotype of rs2032582 locus had a frequency of 43.5% with 0.38 MAF; while the GT and TT genotypes in the control group were 40% and 16.5%, respectively. The GG, GT and TT genotype frequencies in the patients with breast cancer were 45.5%, 12.5% and 26.1%, respectively. An association was observed between the TT genotype of ABCB1/rs2032582 locus and a larger breast cancer tumor size (P < 0.05). However, neither the relationship between the CYP1B1 polymorphism and breast cancer type nor the risk of breast cancer were statistically significant. Our data suggest a potential association of the ABCB1 genetic variant with breast cancer tumor size, however further investigation in a larger population is necessary to show its value as a risk stratification biomarker.

The Therapeutic Potential of MEK1/2 Inhibitors in the Treatment of Gynecological Cancers: Rational Strategies and Recent Progress.

The mitogen-activated protein kinase (MAPK) pathway is among the key factors in numerous cellular processes involved in tumorigenesis, suggesting it as a potential therapeutic target in gynecological cancer. MAPKs connect gene expression pathways and external stimulations. They include a network consisting of Ras, Raf or MAP3K, MEK or MAP2K, ERK or MAPK. Among these, MEK is an attractive molecular target of novel cancer therapeutics as it joints upstream activators and their corresponding downstream targets. MEK inhibitors were among the first inhibitors of the MAPK pathway entering into clinical trials. Several drugs have recently been developed as MEK inhibitors. MEK1/2 inhibitors demonstrate promising efficacy and anticancer activity to treat this malignancy and captured much attention in the past decade. Here, we summarize the role of MAPK/MEK/ERK pathway in the pathogenesis of gynecological cancer, with particular emphasis on MEK inhibitors in clinical settings, including PD-0325901, Selumetinib, Cobimetinib, Refametinib, Trametinib, Pimasertib, MEK162 and WX-554 in gynecologic cancers.

Limb-girdle Muscular Dystrophy and Therapy: Insights into Cell and Gene-based Approaches.

The Limb-Girdle Muscular Dystrophies (LGMD) are genetically heterogeneous disorders, responsible for muscle wasting and severe form of dystrophies. Despite the critical developments in the insight and information of pathomechanisms of limb-girdle muscular dystrophy, any definitive treatments do not exist, and current strategies are only based on the improvement of the signs of disorder and to enhance the life quality without resolving an underlying cause. There is a crucial relationship between pharmacological therapy and different consequences; therefore, other treatment strategies will be required. New approaches, such as gene replacement, gene transfer, exon skipping, siRNA knockdown, and anti-myostatin therapy, which can target specific cellular or molecular mechanism of LGMD, could be a promising avenue for the treatment. Recently, genome engineering strategies with a focus on molecular tools such as CRISPR-Cas9 are used to different types of neuromuscular disorders and show the highest potential for clinical translation of these therapies. Thus, recent advancements and challenges in the field will be reviewed in this paper.

Association of cyclin-dependent kinase inhibitor 2A/B with increased risk of developing breast cancer.

There is a growing body of data reporting the association of genetic alterations in chromosome 9P21 with the risk of developing cancer. In the current study, we studied the association of a genetic variant in CDKN2A/B, rs1333049, with the risk of developing breast cancer. A total of 339 participants with and without breast cancer entered to the study. Genotyping was done by the TaqMan real-time polymerase chain reaction (RT-PCR) method and gene expression analysis was ran by RT-PCR. Our data showed that the minor allele homozygote in the total population was 10%, whereas for heterozygote was 38%. The dominant genetic model demonstrated that individuals with breast cancer had advanced TNM classification. Moreover, the logistic regression revealed that individuals who had CC/CG genotypes might have an enhanced risk of developing breast cancer when compared to the holders of GG genotype (e.g., OR = 2.8; 95% CI,1.4-5.4; p = .001), after regulated for confounders; age and body mass index. Furthermore, our analysis showed that the CDKN2A/B gene was downregulated in patients (p < .001). We showed a meaningful relationship of CDKN2A/B with the risk of breast cancer, cancer, showing the importance of studies in great sample size and several centers for studying the value of the marker as a risk classification in the management of patients with breast cancer.

Association of a genetic variant in ATP-binding cassette sub-family B member 1 gene with poor prognosis in patients with squamous cell carcinoma of the esophagus.

Esophageal cancer is a common cause of death from cancer in men and the eighth most prevalent cancer globally. The morbidity and mortality rates are four times higher in men than in women. Genetic factors are among the susceptibility factors for squamous cell carcinoma of the esophagus. The rs2032582 polymorphism is a triallelic missense variant of the ABCB1 gene, that has been reported to be associated with several cancers. Here we have explored the association of the ABCB1 rs2032582 polymorphism with esophageal squamous cell carcinoma (ESCC) for the first time in a total of 251 subjects, with and without ESCC. Data from patient's record were obtained from the Mashhad University of Medical Sciences, and were used to recruit ESCC patients into the study. A total of 89 ESCC patients and 162 healthy controls were included. DNAs were extracted and genotyped using a TaqMan real-time PCR-based method. Caplan Meier method was applied to analyze patients overall survival, and progression-free survival and log-rank were used in order to compare the results. Logistic regression was used to calculate the association between risk of ESCC and different genotypes. Our data showed that patients with ESCC had a higher frequency of a T/A (TT/TA/AA) genotype for rs2032592 than individuals with GG-genotype. There were no associations between BMI and genotypic frequencies. Furthermore patients with TT/TA/AA genotypes had a poorer disease-free survival (P = 0.016) in comparison with GG genotype. We found a significant association of the ABCB1 rs2032582 polymorphism with prognosis, although further studies in a larger and multicenter setting are needed to value these findings. © 2019 IUBMB Life, 71(9):1252-1258, 2019.

The effects of vitamin D supplementation on indices of glycemic control in Iranian diabetics: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: This systematic review and meta-analysis aimed to assess the effects of vitamin D supplements on indices of glycemic control [homeostatic model assessment-insulin resistance (HOMA-IR), hemoglobin A1C (HbA1C), fasting blood glucose (FBG), and quantitative insulin-sensitivity check index (QUICKI) and lipid profile in diabetic patients. METHODS: Eight databases were searched, for randomized controlled trials (RCTs) or cross-sectional and cohort studies that have been published up to December 2017. We used the comprehensive meta-analysis (CMA) software for all statistical analysis and used the I2 index for assessing heterogeneity. A p value of <0.05 was considered as statistically significant. RESULTS: We found 621 articles, and after the exclusion of ineligible publications, 82 studies remained to be assessed of which 37 were used for meta-analysis. Vitamin D supplementation was associated with a significant improvement in FBG (p = 0.001 and 95% CI: -0.526 to -0.136) and HbA1C (p = 0.003 and 95% CI: 1.719 to -0.361) in individuals with type 2 diabetes mellitus (T2DM); while in women with gestational diabetes mellitus (GDM) the reduction in FBG (p = 0.071 and 95% CI: -0.873 to -0.035) and HbA1C (p = 0.199 and 95% CI: 3.270 to 0.681) failed to reach statistical significance. Treatment with vitamin D supplements was associated with an improvement in HOMA-IR in pregnant diabetic women (p = 0.028 and 95% CI: 0.924 to -0.053) and for individuals with diabetes mellitus (p = 0.005 and 95% CI: 1.772 to -0.319). The pooled result of the cross-sectional meta-analysis indicated that serum vitamin D concentrations were significantly lower in diabetic patients than in healthy controls (p = 0.018 and 95% CI: 0.587 to -0.054). CONCLUSION: This meta-analysis suggests that vitamin D supplementation improves indices of glycemic control (FBG, HOMA-IR, and HbA1C) in patients with diabetes mellitus. Hence, vitamin D supplements may be of potential therapeutic value in diabetic patients, as an adjuvant therapy along with other treatments.

Association of TNF-308 G>A polymorphism located in tumor necrosis factor a with the risk of developing cervical cancer and results of pap smear.

Tumor necrosis factor a (TNFa) is an inflammatory cytokine that plays a crucial role in the immune response and the progression of cervical lesions. There is a growing body of data evaluating the value of a genetic variant in the TNFa gene with the risk of developing cervical cancer. The aim of this study was to explore the association of a variant, TNF-308 G>A, residing in the TNFa gene with cervical cancer. A total of 91 women with cervical cancer and 161 women as the control group were recruited. DNA was extracted, and Taqman®-probes-based assay was used for genotyping. Our results showed that the minor allele frequency was 0.3 in total population, and the frequency of minor allele A was more in the case group compared with the control. The regression models in different genetic models also revealed that the allele A is a potential risk factor for the development of cervical cancer. In particular, in the dominant model, patients with AG and AA genotypes had a higher risk of developing cervical cancer with odds ratio (OR) of 2.75 (95% confidence interval [CI]: 1.57-4.83, <0.001) and OR of 7.27 (95%CI: 2.5-20.8, <0.001), compared with the GG genotype. Moreover, a similar outcome was obtained for smear test results. Our study demonstrated that TNF-308 G>A located on TNF-a was associated with the risk of cervical cancer, supporting further studies in a larger population and multicenter setting to show the value of emerging markers as risk stratification biomarkers in cervical cancer.

High dose vitamin D supplementation can improve menstrual problems, dysmenorrhea, and premenstrual syndrome in adolescents.

Vitamin D has a crucial role in female reproduction, possibly through its effects on calcium homeostasis, cyclic sex steroid hormone fluctuations, or neurotransmitter function. We have assessed the effects of vitamin D supplementation on dysmenorrhea and premenstrual syndrome (PMS) in adolescents. In this study, 897 adolescent girls living in Mashhad and Sabzevar, Iran, received nine high-dose vitamin D supplements (as 50,000 IU/week of cholecalciferol) and were followed up over 9 weeks. We evaluated the effect of vitamin D supplementation on individuals in four categories: those with only PMS; individuals with only dysmenorrhea; subjects with both PMS and dysmenorrhea and normal subjects. The prevalence of PMS after the intervention fell from 14.9% to 4.8% (p < .001). Similar results were also found for the prevalence of subjects with dysmenorrhea (35.9% reduced to 32.4%), and in subjects with both PMS and dysmenorrhea (32.7% reduced 25.7%). Vitamin D supplementation was associated with a reduction in the incidence of several symptoms of PMS such as backache and tendency to cry easily as well as decrement in pain severity of dysmenorrhea (p < .05). High dose vitamin D supplementation can reduce the prevalence of PMS and dysmenorrhea as well as has positive effects on the physical and psychological symptoms of PMS.

Tumor-derived exosomes: Potential biomarker or therapeutic target in breast cancer?

Exosomes are released by normal and tumour cells, including those involved in breast cancer, and provide a means of intercellular communications. Exosomes with diameters ranging between 30-150 nm are involved in transferring biological information, via various lipids, proteins, different forms of RNAs, and DNA from one cell to another, and this can result in reprogramming of recipient cell functions. These vesicles are present in all body fluids, for example, blood plasma/serum, semen, saliva, cerebrospinal fluid, breast milk, and urine. It has been recently reported that these particles are involved in the development and progression of different tumor types, including breast cancer. Furthermore, it has been suggested that exosomes have the potential to be used as drug transporters, or as biomarkers. This review highlights the potential roles of exosomes in normal and breast cancer cells and their potential applications as biomarkers with special focus on their potential applications in treatment of breast cancer.