MicroRNAs in breast cancer: Roles, functions, and mechanism of actions.

Breast cancer is one of the most lethal malignancies in women in the world. Various factors are involved in the development and promotion of the malignancy; most of them involve changes in the expression of certain genes, such as microRNAs (miRNAs). MiRNAs can regulate signaling pathways negatively or positively, thereby affecting tumorigenesis and various aspects of cancer progression, particularly breast cancer. Besides, accumulating data demonstrated that miRNAs are a novel tool for prognosis and diagnosis of breast cancer patients. Herein, we will review the roles of these RNA molecules in several important signaling pathways, such as transforming growth factor, Wnt, Notch, nuclear factor-κ B, phosphoinositide-3-kinase/Akt, and extracellular-signal-regulated kinase/mitogen activated protein kinase signaling pathways in breast cancer.

Critical roles of long noncoding RNAs in breast cancer.

Breast cancer is a major clinical challenge that affects a wide range of the female population and heavily burdens the health system. In the past few decades, attempts have been made to understand the etiology of breast cancer, possible environmental risk factors, and the genetic predispositions, pathogenesis, and molecular aberrations involved in the process. Studies have shown that breast cancer is a heterogeneous entity; each subtype has its specific set of aberrations in different cell signaling pathways, such as Notch, Wnt/ß-catenin, transforming growth factor-ß, and mitogen-activated protein kinase pathways. One novel group of molecules that have been shown to be inducted in the regulation of multiple cell signaling pathways is the long noncoding RNAs (lncRNAs). These molecules have important implications in the regulation of multiple signaling pathways by interacting with various genes, affecting the transcription process, and finally, playing roles in posttranslational control of these genes. There is growing evidence that lncRNAs are involved in the process of breast cancer formation by effecting the aforementioned signaling pathways, and that this involvement can have significant diagnostic and prognostic values in clinical contexts. The present review aims to elicit the significance of lncRNAs in the regulation of cell signaling pathways, and the resulting changes in cell survival, proliferation, and invasion, which are the hallmarks of breast cancer.

Human BCL10 Deficiency due to Homozygosity for a Rare Allele.

In 2014, a child with broad combined immunodeficiency (CID) who was homozygous for a private BCL10 allele was reported to have complete inherited human BCL10 deficiency. In the present study, we report a new BCL10 mutation in another child with CID who was homozygous for a BCL10 variant (R88X), previously reported as a rare allele in heterozygosis (minor allele frequency, 0.000003986). The mutant allele was a loss-of-expression and loss-of-function allele. As with the previously reported patient, this patient had complete BCL10 deficiency. The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis. Cellular and immunological phenotypes were similar to those of the previous patient. TLR4, TLR2/6, and Dectin-1 responses were found to depend on BCL10 in fibroblasts, and final maturation of T cell and B cell maturation into memory cells was affected. Autosomal-recessive BCL10 deficiency should therefore be considered in children with CID.

Overcoming multidrug resistance in cancer: Recent progress in nanotechnology and new horizons.

Multidrug resistance (MDR), defined as the ability of cancer cells to gain resistance to both conventional and novel chemotherapy agents, is an important barrier in treating malignancies. Initially, it was discovered that cellular pumps dependent on ATP were the cause of resistance to chemotherapy, and further studies have found that other mechanisms such as increased metabolism of drugs, decreased drug entry, and defective apoptotic pathways are involved in this process. MDR has been the focus of numerous initiatives and countless studies have been undertaken to better understand MDR and formulate strategies to overcome its effects. The current review highlights various nano-drug delivery systems including polymeric/solid lipid/mesoporous silica/metal nanoparticles, dendrimers, liposomes, micelles, and nanostructured lipid carriers to overcome the mechanism of MDR. Nanoparticles are novel gateways to enhance the therapeutic efficacy of anticancer agents at the target site of action due to their tumor-targeting abilities, which can limit the unwanted systemic effects of chemotherapy agents and also reduce drug resistance. Additionally, other innovative strategies including RNA interference as a biological process used to inhibit or silence specific gene expression, natural products as MDR modulators with little systemic toxic effects, which interfere with the functions of proteins involved in drug efflux, and physical approaches such as combination of conventional drug administration with thermal/ultrasound/photodynamic strategies are also highlighted.

The prevalence of latent and acute toxoplasmosis in HIV-infected pregnant women: A systematic review and meta-analysis.

OBJECTIVE: HIV in pregnancy is not only important for mother-to-child HIV transmission, but also it assumes additional importance because HIV increases susceptibility to opportunistic infections, leading to increased morbidity and mortality in mothers and neonates. Toxoplasmosis is one of the most important opportunistic infections in HIV-infected pregnant women. The present study was undertaken to assess the prevalence of latent toxoplasmosis (LT) and acute toxoplasmosis (AT) infection in HIV-infected pregnant women. METHODS: PubMed/MEDLINE, Scopus, Web of Science, EMBASE and SciELO were searched to identify relevant studies. A random-effects model was used to estimate the overall and subgroup-pooled prevalences across studies. Heterogeneity between studies was assessed via the I2 test. RESULTS: A total of 14 articles that included 3256 subjects in nine countries met the inclusion criteria. The overall prevalence rates of LT and AT in HIV-infected pregnant women were 45.7% (95% CI, 32.3-59.7%) and 1.1% (95% CI, 0.4-3.2%), respectively. The findings indicate that, worldwide, approximately 559,000 and 13,450 HIV-infected pregnant women are affected by LT and AT, respectively. From this review, it is estimated that approximately 3432 babies annually could be born with congenital toxoplasmosis (CT) from HIV-infected pregnant mothers. CONCLUSIONS: The present study indicates that a large number of HIV-infected mothers are affected by LT and AT. This can lead to adverse complications such toxoplasmic encephalitis in mothers and CT in neonates. Our results suggest a need for screening programs using well-validated diagnostic platforms for both LT and AT for all HIV-infected pregnant women.

MicroRNAs, DNA damage response and ageing.

Ageing is a multifactorial and integrated gradual deterioration affecting the most of biological process of cells. MiRNAs are differentially expressed in the cellular senescence and play important role in regulating of genes expression involved in features of ageing. The perception of miRNAs functions in ageing regulation can be useful in clarifying the mechanisms underlying ageing and designing of therapeutic strategies. The preservation of genomic integrity through DNA damage response (DDR) is related to the process of cellular senescence. The recent studies have shown that miRNAs has directly regulated the expression of numerous proteins in DDR pathways. In this review study, DDR pathways, miRNA biogenesis and functions, current finding on DDR regulations, molecular biology of ageing and the role of miRNAs in these processes have been studied. Finally, a brief explanation about the therapeutic function of miRNAs in ageing regarding its regulation of DDR has been provided.

The critical roles of lncRNAs in the pathogenesis of melanoma.

Long non-coding RNAs (lncRNAs) embrace a huge fraction of human transcripts and participate in the pathogenesis of human disorders especially malignant conditions. Malignant melanoma, as the most fatal type of cutaneous malignnacies, is associated with dysregulation of several lncRNAs including PVT1, H19, MALAT1, and CCAT1. Moreover, a portion of lncRNAs are exclusively expressed in melanoma cell lines. Expression levels of several lncRNAs are associated with TNM stage, tumor size and progression of melanoma. Thus, these lncRNAs are regarded as biomarkers for this malignancy. Peripheral transcript levels of a number of lncRNAs, such as PVT1, SNHG5 and SPRY4-IT1, could distinguish melanoma patients from unaffected persons with appropriate sensitivity and specificity values. Moreover, expression levels of numerous lncRNAs in tissue biopsies could differentiate malignant samples from benign samples. Based on the results of both cell line and in vivo studies, lncRNAs regulate critical pathways in the carcinogenesis of melanoma, such as the PI3K/Akt and NF-κB signaling pathways, and are involved in the modulation of response to chemotherapeutic agents. Here we review the existing information on the role of lncRNAs in malignant melanoma.

Health-related Quality of Life and Associated Factors Among Thalassemia Major Patients, Southeast of Iran.

Low quality of life (QOL) is a feature that has been overlooked in thalassemia major (TM) patients. Our aim was to assess QOL in school-aged TM patients in Zabol city and surrounding rural areas in southeast of Iran. The study was performed in 2014. QOL was evaluated using Pediatric Quality of Life Inventory 4 (PedsQL4) questionnaire addressing physical, emotional, social, and educational, along with psychological health in 80 TM patients. Also, 80 age-matched and sex-matched subjects without any chronic illness served as control group. Mean age of the patients was 11.7±4.1 years old. Total QOL scores was 51.4±13.3 in the patients. In comparison, mean value of total QOL score in controls was 91.1±3.3 (P<0.0001). Poor and moderate QOL were observed in 44.7% and 48.7% of the patients, respectively. Mean functioning scores for physical, emotional, social, educational, and psychological dimensions in the patients were 56.2±119, 69.6.4±23.3, 27.1±22.1, 52.3±18.1, and 48.9±11.8, respectively. The lowest level of QOL was related to the social field (81.3% with less than average score), while the highest QOL was related to the emotional aspect (58.8% with good QOL; >75 scores). Overall, female sex, poor compliance with chelation therapy, and residency in urban areas were significantly associated with poor QOL. In conclusion, providing a psychiatric health package seems to be essential for improving QOL in TM patients, especially in social field.

Oral Administration of Cancer Vaccines: Challenges and Future Perspectives.

Cancer vaccines, a burgeoning strategy in cancer treatment, are exploring innovative administration routes to enhance patient and medical staff experiences, as well as immunological outcomes. Among these, oral administration has surfaced as a particularly noteworthy approach, which is attributed to its capacity to ignite both humoral and cellular immune responses at systemic and mucosal tiers, thereby potentially bolstering vaccine efficacy comprehensively and durably. Notwithstanding this, the deployment of vaccines through the oral route in a clinical context is impeded by multifaceted challenges, predominantly stemming from the intricacy of orchestrating effective oral immunogenicity and necessitating strategic navigation through gastrointestinal barriers. Based on the immunogenicity of the gastrointestinal tract, this review critically analyses the challenges and recent advances and provides insights into the future development of oral cancer vaccines.

Increased frequency of HLA-A*02 in patients with atherosclerosis is associated with VZV seropositivity.

BACKGROUND: HLA molecules are inherited key molecules in the immune inflammation and specific responses to environmental pathogens. We investigated the association of HLA-A alleles with Varicella zoster virus (VZV) seropositivity in patients with atherosclerosis (AS). MATERIALS AND METHODS: Plasma Anti-VZV IgG and molecular HLA type were detected in 203 (100 AS+ and 103 AS-) individuals. RESULTS: Of 100 AS+ individuals, 66 were anti-VZV+ and 34 were anti-VZV-. Of 103 age/sex-matched AS- individuals, 59 were anti-VZV+ and 44 were anti-VZV-. Anti-VZV-IgG in AS+ cases was higher than AS- controls (p = .034). The mean anti-VZV IgG in HLA-A*02+AS+ individuals was higher than HLA-A*02+AS- controls (p < .001). HLA-A*02 was associated with VZV-seropositivity (p = .01) in AS+ patients. A higher frequency of HLA-A*02-allele in AS+ patients compared to AS- controls (p = .015) and an accumulation of HLA-A*02-allele in AS+ anti-VZV+ group (33.3%, p = .004) was observed. CONCLUSIONS: HLA-A alleles and immune responses to VZV are associated with clinical atherosclerosis.

A review of the role of genetic factors in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an acute inflammatory polyradiculoneuropathy syndrome. Several genetic and environmental risk factors have been recognized for GBS. AS GBS is an immune-related disorder, abnormal functions of T cells, production of autoantibodies, and dysregulation of gene expression have been detected in GBS patients. Based on the critical role of human leukocyte antigen (HLA) in the regulation of immune responses, HLA alleles are among the mostly investigated loci in GBS. A number of polymorphisms within different genes, especially those linked with the regulation of immune responses, have been associated with GBS in different populations. Moreover, several studies have demonstrated abnormal expression of cytokine-coding genes in this disorder. Investigations in the animal model of GBS have also verified the aberrant regulation of Th1/Th2/Th17/Treg cytokines. In the current review, we describe the information about the role of these factors in GBS.

Association Analysis of ANRIL Polymorphisms and Haplotypes with Autism Spectrum Disorders.

Autism spectrum disorder (ASD) has been shown to have a complex inheritance. Several single-nucleotide polymorphisms (SNPs) have been shown to be associated with risk of this neurodevelopmental disorder. In the current study, we genotyped four SNPs in a genomic hotspot for human disorders. The selected SNPs were located in adjacency of the antisense noncoding RNA in the INK4 locus (ANRIL) and have been shown to be associated with a number of human disorders. Genotyping was performed in 420 ASD cases and 420 normally developed children. After correction of P values for multiple comparisons, there was no significant difference in frequencies of rs1333045, rs1333048, rs4977574, and rs10757278 alleles, genotypes, or haplotypes between ASD children and children with normal development. However, one estimated haplotype (T A A A haplotype corresponding to rs1333045, rs1333048, rs4977574, and rs10757278 SNPs, respectively) tended to be more prevalent among cases compared with controls (OR (95% CI) = 1.77 (1.19-2.64), adjusted P value = 0.07). Besides, the T A G G tended to be less common among ASD cases compared with controls (OR (95% CI) = 0.64 (0.47-0.87), adjusted P value = 0.07). Although we could not detect significant difference in alleles, genotypes, or haplotypes frequencies between cases and controls, the trend toward association between two haplotypes and ASD risk implies that there might be a putative causative variant in the mentioned haplotypes whose association with ASD could be determined in larger cohorts of patients.

Dysregulation of NF-κB-Associated lncRNAs in Multiple Sclerosis Patients.

Long non-coding RNAs (lncRNAs) have been reported to participate in the pathogenesis of several complex disorders such as immune-related disorders. Multiple sclerosis (MS) as an inflammatory disorder of the central nervous system has been associated with aberrant expression of several lncRNAs. In the current study, we assessed expression of NF-κB-, autophagy-, and obesity-associated lncRNAs/genes and two inflammatory cytokines in the peripheral blood of MS patients and healthy controls. LNC-MKI67IP was down-regulated in total MS patients compared with total controls (P value < 0.0001). However, when comparing its expression in a gender-based manner, no significant difference was found between patients and controls. Expression of HNF1A-AS1 was significantly lower in total MS patients and patients of both sexes when compared with the matched controls (P value < 0.0001; P value = 0.03; P value = 0.004, respectively). Expression of LINC00305 had a similar pattern to HNF1A-AS1 (P value < 0.0001; P value = 0.005; P value < 0.0001, respectively). Expressions of other assessed NF-κB associated lncRNAs were not different between cases and controls. Expression of IL-1B was significantly lower in total MS patients compared with total controls (P value < 0.0001). Such decreased expression was detected in female patients compared with female controls as well (P value < 0.0001). Expression of IL-6 was not different between cases and controls. Expression of CEBPA was higher in total MS patients compared with controls (P value = 0.047). However, when dividing study participants into male and female subgroups, no significant difference was detected between cases and gender-matched controls. There were no significant difference in the expression of any assessed autophagy-associated lncRNAs between cases and controls. ATG5, CEBPA, HNF1A-AS1, IL-1B, LINC00305, and LNC-MKI67IP could differentiate disease status with diagnostic power values of 0.781, 0.582, 0.744, 0.76, 0.926, and 0.703, respectively. Expression levels of ADINR and CHAST were correlated with age of MS patients and disease duration, respectively (r = 0.33, P < 0.0001; r = 0.34, P < 0.0001, respectively). The present study highlighted the role of a number lncRNAs in the pathogenesis of MS and supported the previous data regarding aberrant expression of these transcripts in this immune-related disorder.

Serum Calprotectin as a Blood-Based Biomarker for Monitoring Knee Osteoarthritis at Early but Not Late Stages.

OBJECTIVE: The identification of early-stage osteoarthritis (OA) is crucial for the deceleration of its progression; however, no reliable biomarker is available for this purpose. The current study aimed to determine the role of serum calprotectin in the detection of early-stage knee OA. DESIGN: In a case-control study, serum samples were collected from 84 patients with primary bilateral knee OA and 52 healthy controls. The radiographic grading of knee OA was performed using the Kellgren-Lawrence classification system. Serum concentrations of calprotectin were measured using an enzyme-linked immunosorbent assay. RESULTS: The mean serum calprotectin level was 2908 ± 2516 ng/mL in OA patients and 901 ± 875 ng/mL in healthy control subjects (P < 0.001). Mean serum calprotectin levels were significantly higher in the lower stages of OA: 3740 ± 2728 ng/mL in OA grade I, 3100 ± 2084 ng/mL in OA grade II, 2246 ± 1418 ng/mL in OA grade III, and 2035 ± 765 ng/mL in OA grade IV (P = 0.047). Serum calprotectin levels were significantly higher in patients with a disease duration <42 months compared with those with a disease duration >42 months (P = 0.043). CONCLUSION: Serum calprotectin level increases significantly in the early stages of OA and shows a reverse association with disease severity. Therefore, it could be suggested as a promising blood-based marker for early-stage knee OA.

DNA damage response and breast cancer development: Possible therapeutic applications of ATR, ATM, PARP, BRCA1 inhibition.

Breast cancer is the most common and significant cancers in females regarding the loss of life quality. Similar to other cancers, one of the etiologic factors in breast cancer is DNA damage. A plethora of molecules are responsible for sensing DNA damage and mediating actions which lead to DNA repair, senescence, cell cycle arrest and if damage is unbearable to apoptosis. In each of these, aberrations leading to unrepaired damage was resulted in uncontrolled proliferation and cancer. Another cellular function is autophagy defined as a process eliminating of unnecessary proteins in stress cases involved in pathogenesis of cancer. Knowing their role in cancer, scholars have tried to develop strategies in order to target DDR and autophagy. Further, the interactions of DDR and autophagy plus their regulatory role on each other have been focused simultaneously. The present review study has aimed to illustrate the importance of DDR and autophagy in breast cancer according to the related studies and uncover the relation between DDR and autophagy and its significance in breast cancer therapy.

A review on anti-cancer properties of Quercetin in breast cancer.

Breast cancer is one of the well-known malignant tumors among women. In spite of attempts to classifying breast cancer according to its histological and molecular properties, it is almost considered as a dilemma in treatment. Nowadays, public and medical attentions have primary focused on foods with anti-cancer properties to alleviate the cancer problems. Flavonoid components such as Quercetin (Qu) as dietary substances with high attention of ordinary people might provide potential of alternative or complementary medicine in breast cancer. With regard to the wide range of health benefits of Qu, researchers have been generally convinced to bring Qu as natural compounds in cancer therapy. Moreover, the high cost of standard cancer treatments and the failure of most conventional treatments have led the medical community to pursue cost-effective prevention and treatment. As a result, a great deal of concentration is attracted to diet/cancer reciprocal action. Therefore, this review study has aimed to identify what has revealed the critical properties of Qu such as anti-inflammatory, anti-oxidant, and even its effect on proliferation, angiogenesis, or apoptosis that are considered as anti-tumor property to enhance breast cancer treatment.

Targeting miRNAs by polyphenols: Novel therapeutic strategy for aging.

Regarding the importance of genetic and epigenetic factors in regulation of aging process, different expression pattern of non-coding RNAs in aging could be investigated. Accordingly, micro RNAs (miRNAs) with a wide range of physiological functions as well as a significant footprint in many diseases have been demonstrated to be down or upregulated during the aging process. Therefore, age-associated microRNAs and their targets have potentially detected the accelerated aging and predicted the risks for age-related diseases. Polyphenols as important antioxidants in human dietary observed in fruits and some beverages have beneficial effects on longevity and aging. Considering miRNAs as an interesting mediator in modulating polyphenols' biological effects, targeting miRNAs which is using polyphenols could be a novel strategy for aging.

MicroRNAs as regulators of ERK/MAPK pathway: A comprehensive review.

The ERK/MAPK cascade is one the four distinctive MAPK cascades which transmit extracellular signals to intracellular targets. This cascade has an important role in the regulation of several fundamental processes such as proliferation, differentiation and cell response to diverse extrinsic stresses. Moreover, several studies have shown participation of this cascade in the pathogenesis of cancer. Recent investigations have unraveled interaction between microRNAs (miRNAs) and ERK/MAPK cascade. These transcripts reside in both upstream and downstream of this cascade, regulating or being regulated by ERK/MAPK proteins. In the current review, we summarize the role of miRNAs in the regulation of ERK/MAPK and their contribution in the pathogenesis of human disorders with particular focus on cancers.

A Single Nucleotide Polymorphism Within Molybdenum Cofactor Sulfurase Gene Is Associated With Neuropsychiatric Conditions.

BACKGROUND: Molybdenum cofactor sulfurase (MOCOS) is an enzyme participating in purine metabolism. The aim of current study was to evaluate the role of a single nucleotide polymorphism (SNP) in the coding gene (rs594445) in mood disorders and methamphetamine addiction. METHODS: This SNP was genotyped in 200 persons with methamphetamine addiction, 85 patients with bipolar disorder 1 (BP1), 78 patients with BP2, 33 patients with major depressive disorder (MDD) and 200 age-/sex-matched normal subjects using the tetra-primer amplification-refractory mutation system (ARMS)-PCR technique. RESULTS: The rs594445 was associated with methamphetamine addiction in co-dominant model [A/A vs C/C: OR (95% CI) = 0.466 (0.252-0.864), P-value = 0.014; C/A vs C/C: OR (95% CI) = 0.641 (0.418-0.981), P-value = 0.04]. This SNP was also associated with this trait in dominant model [OR (95% CI) = 0.591 (0.398-0.879), P-value = 0.009]. The A allele of rs594445 had a protective role against methamphetamine addiction [A vs C: OR (95% CI) = 0.645 (0.48-0.866), P-value = 0.004]. The rs594445 was associated with BP1 in co-dominant model [C/A vs C/C: OR (95% CI) = 0.423 (0.230-0.778), P-value = 0.005]. However, the associations were insignificant in other inheritance models. CONCLUSION: Finally, there were no significant associations between the mentioned SNP and risk of BP2 or MDD in any inheritance model. The present project highlights the role rs594445 in two psychiatric conditions and implies the presence of common genetic factors for these disorders.