Milk-Derived Extracellular Vesicles: Biomedical Applications, Current Challenges, and Future Perspectives.

Extracellular vesicles (EVs) are nano to-micrometer-sized sacs that are released by almost all animal and plant cells and act as intercellular communicators by transferring their cargos between the source and target cells. As a safe and scalable alternative to conditioned medium-derived EVs, milk-derived EVs (miEVs) have recently gained a great deal of popularity. Numerous studies have shown that miEVs have intrinsic therapeutic actions that can treat diseases and enhance human health. Additionally, they can be used as natural drug carriers and novel classes of biomarkers. However, due to the complexity of the milk, the successful translation of miEVs from benchtop to bedside still faces several unfilled gaps, especially a lack of standardized protocols for the isolation of high-purity miEVs. In this work, by comprehensively reviewing the bovine miEVs studies, we provide an overview of current knowledge and research on miEVs while highlighting their challenges and enormous promise as a novel class of theranostics. It is hoped that this study will pave the way for clinical applications of miEVs by addressing their challenges and opportunities.

Nanotechnology and nano-sized tools: Newer approaches to circumvent oncolytic adenovirus limitations.

Oncolytic adenoviruses (OAds), engineered Ads preferentially infect and lyse tumor cells, have attracted remarkable attention as immunotherapy weapons for the treatment of various malignancies. Despite hopeful successes in preclinical investigations and translation into clinical phases, they face some challenges that thwart their therapeutic effectiveness, including low infectivity of cancer cells, liver sequestration, pre-existing neutralizing antibodies, physical barriers to the spread of Ads, and immunosuppressive TME. Nanotechnology and nano-sized tools provide several advantages to overcome these limitations of OAds. Nano-sized tools could improve the therapeutic efficacy of OAds by enhancing infectivity and cellular uptake, targeting and protecting from pre-existing immune responses, masking and preventing liver tropism, and co-delivery with other therapeutic agents. Herein, we reviewed the constructs of various OAds and their application in clinical trials, as well as the limitations they have faced. Furthermore, we emphasized the potential applications of nanotechnology to solve the constraints of OAds to improve their anti-tumor activities.

Mixed oral biofilms are controlled by the interspecies interactions of Fusobacterium nucleatum.

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) is an integral component of supra- and subgingival biofilms, especially more prevalent in subgingival areas during both periodontal health and disease. AIMS: In this review, we explore the physical, metabolic, and genetic interactions that influence the role of F. nucleatum in the formation of mixed oral biofilms. The role of F. nucleatum in antibiotic resistance in oral biofilms was discussed and some therapeutic strategies were proposed. METHODS: PubMed, Scopus, Google Scholar, and the Web of Science were extensively searched for English-language reports. RESULTS: F. nucleatum-derived proteins such as RadD, Fap2, FomA, and CmpA are involved in direct interactions contributing to biofilm formation, while autoinducer-2 and putrescine are involved in metabolic interactions. Both groups are essential for the formation and persistence of oral biofilms. This study highlights the clinical relevance of targeted interactions of F. nucleatum in supra- and subgingival oral biofilms. CONCLUSIONS: By focusing on these interactions, researchers and clinicians can develop more effective strategies to prevent biofilm-related disease and reduce the spread of antibiotic resistance. Further research in this area is warranted to explore the potential therapeutic interventions that can be derived from understanding the interactions of F. nucleatum in oral biofilm dynamics.

Accurate computational design of three-dimensional protein crystals.

Protein crystallization plays a central role in structural biology. Despite this, the process of crystallization remains poorly understood and highly empirical, with crystal contacts, lattice packing arrangements and space group preferences being largely unpredictable. Programming protein crystallization through precisely engineered side-chain-side-chain interactions across protein-protein interfaces is an outstanding challenge. Here we develop a general computational approach for designing three-dimensional protein crystals with prespecified lattice architectures at atomic accuracy that hierarchically constrains the overall number of degrees of freedom of the system. We design three pairs of oligomers that can be individually purified, and upon mixing, spontaneously self-assemble into >100 µm three-dimensional crystals. The structures of these crystals are nearly identical to the computational design models, closely corresponding in both overall architecture and the specific protein-protein interactions. The dimensions of the crystal unit cell can be systematically redesigned while retaining the space group symmetry and overall architecture, and the crystals are extremely porous and highly stable. Our approach enables the computational design of protein crystals with high accuracy, and the designed protein crystals, which have both structural and assembly information encoded in their primary sequences, provide a powerful platform for biological materials engineering.

Polymeric nanoparticles for DNA vaccine-based cancer immunotherapy: a review.

Cancer is one of the leading causes of death and mortality in the world. There is an essential need to develop new drugs or therapeutic approaches to manage treatment-resistant cancers. Cancer immunotherapy is a type of cancer treatment that uses the power of the body's immune system to prevent, control, and eliminate cancer. One of the materials used as a vaccine in immunotherapy is DNA. The application of polymeric nanoparticles as carriers for DNA vaccines could be an effective therapeutic approach to activate immune responses and increase antigen presentation efficiency. Various materials have been used as polymeric nanoparticles, including: chitosan, poly (lactic-co-glycolic acid), Polyethylenimine, dendrimers, polypeptides, and polyesters. Application of these polymer nanoparticles has several advantages, including increased vaccine delivery, enhanced antigen presentation, adjuvant effects, and more sustainable induction of the immune system. Besides many clinical trials and commercial products that were developed based on polymer nanoparticles, there is still a need for more comprehensive studies to increase the DNA vaccine efficiency in cancer immunotherapy using this type of carrier.

VEGFR2 Mimicking Peptide Inhibits the Proliferation of Human Umbilical Vein Endothelial Cells (Huvecs) by Blocking VEGF.

INTRODUCTION: A variety of key human physiological processes rely on angiogenesis, ranging from reproduction and fetal growth to wound healing and tissue repair. Furthermore, this process significantly contributes to tumor progression, invasion, and metastasis. As the strongest inducer of angiogenesis, Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) are targets of therapeutic research for blocking pathological angiogenesis. OBJECTIVE: Preventing the interaction between VEGF and VEGFR2 by a peptide is a promising strategy for developing antiangiogenic drug candidates. This study was aimed at designing and evaluating VEGF-targeting peptides using in silico and in vitro techniques. METHODS: The VEGF binding site of VEGFR2 was considered a basis for peptide design. The interaction of VEGF and all three peptides derived from VEGFR2 were analyzed using ClusPro tools. In a complex with VEGF, the peptide with a higher docking score was evaluated to confirm its stability using molecular dynamics (MD) simulation. The gene coding for the selected peptide was cloned and expressed in E. coli BL21. The bacterial cells were cultured on a large scale, and the expressed recombinant peptide was purified using Ni-NTA chromatography. Refolding of the denatured peptide was carried out by the stepwise removal of the denaturant. The reactivity of peptides was confirmed using western blotting and enzyme-linked immunosorbent assay (ELISA) assays. Finally, the inhibition potency of the peptide on human umbilical vein endothelial cells was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- 2H-tetrazolium bromide (MTT) assay. RESULTS: Among three peptides, the peptide with the best docking pose and the highest affinity for VEGF was selected for further studies. Then the stability of the peptide was confirmed over the 100 ns MD simulation. After in silico analyses, the selected peptide was presented for in vitro analysis. Expression of the selected peptide in E. coli BL21 resulted in a pure peptide with a yield of approximately 200 µg/ml. Analysis by ELISA revealed the high reactivity of the peptide with VEGF. Western blot analysis confirmed the specific reactivity of selected peptides with VEGF. The MTT assay revealed the growth inhibitory effect of the peptide on human umbilical vein endothelial cells with an IC50 value of 247.8 µM. CONCLUSION: In summary, the selected peptide demonstrated a promising inhibitory effect on human umbilical vein endothelial cells that could be a valuable anti-angiogenic candidate for further assessment. Additionally, these in silico and in vitro data provide new insights into peptide design and engineering.

Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies.

Growth factors and cytokines signal by binding to the extracellular domains of their receptors and drive association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affects signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo designed fibroblast growth-factor receptor (FGFR) binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca2+ release and MAPK pathway activation. The high specificity of the designed agonists reveal distinct roles for two FGFR splice variants in driving endothelial and mesenchymal cell fates during early vascular development. The ability to incorporate receptor binding domains and repeat extensions in a modular fashion makes our designed scaffolds broadly useful for probing and manipulating cellular signaling pathways.

Nanovaccines for cancer immunotherapy: Focusing on complex formation between adjuvant and antigen.

As an interesting cancer immunotherapy approach, cancer vaccines have been developed to deliver tumor antigens and adjuvants to antigen-presenting cells (APCs). Although the safety and easy production shifted the vaccine designing platforms toward the subunit vaccines, their efficacy is limited due to inefficient vaccine delivery. Nanotechnology-based vaccines, called nanovaccines, address the delivery limitations through co-delivery of antigens and adjuvants into lymphoid organs and APCs and their intracellular release, leading to cross-presentation of antigens and induction of potent anti-tumor immune responses. Although the nanovaccines, either as encapsulating agents or biomimetic nanoparticles, exert the desired anti-tumor activities, there is evidence that the mixing formulation to form nanocomplexes between antigens and adjuvants based on the electrostatic interactions provokes high levels of immune responses owing to Ags' availability and faster release. Here, we summarized the various platforms for developing cancer vaccines and the advantages of using delivery systems. The cancer nanovaccines, including nanoparticle-based and biomimetic-based nanovaccines, are discussed in detail. Finally, we focused on the nanocomplexes formation between antigens and adjuvants as promising cancer nanovaccine platforms.

An Anti-TAZ Monoclonal Antibody Recognizing Cell Surface Expressed TAZ Protein in Human Tumor Cells.

Background: WWTR1 or TAZ is a transcriptional co-activator protein expressed in cytoplasm which functions as the main downstream effector of the Hippo signaling pathway. This pathway is an evolutionally conserved signal cascade, which plays a pivotal role in organ size control and tumorigenesis. Ectopic expression of TAZ has already been observed in many malignancies, while the ectopic localization of TAZ is reported for the first time. The aim of this study was to produce a specific monoclonal antibody (mAb) against a synthetic peptide derived from WWTR1 protein to be used as a research tool in human carcinomas. Methods: A 21-mer synthetic peptide (derived from human TAZ protein) was used for immunization of BALB/c mice after conjugation with Keyhole Limpet Haemocyanin (KLH) using hybridoma technology. The generated mAb reacted with the immunizing peptide employing ELISA assay. The reactivity of the antibody with native TAZ protein was assessed through Western blot, immunocytochemistry, and flow cytometry using different cancer cell lines. Results: The produced mAb could recognize the immunizing peptide in ELISA and Kaff was 0.6×10-9 M. The produced anti-TAZ mAb unlike available commercial anti-TAZ antibody, was capable of specifically recognizing cell surface TAZ in human carcinoma cell lines including MCF-7, Raji, and A431 in Western blot, immunocytochemistry, and flow cytometry assays. As expected, no reactivity was observed using normal Peripheral Blood Mononuclear Cell (PBMC) from healthy donors. Conclusion: Based on the results, TAZ is ectopically expressed on the surface of tumor cell lines which is not the case in normal cells. The generated mAb has a potential to be used as a research tool in studying the expression of TAZ in human carcinomas in different applications.

Amoxicillin-docosahexaenoic acid encapsulated chitosan-alginate nanoparticles as a delivery system with enhanced biocidal activities against Helicobacter pylori and improved ulcer healing.

Encapsulation of amoxicillin (AMX) for drug delivery against Helicobacter pylori infection and aspirin-induced ulcers in rat's stomachs was performed using docosahexaenoic acid (DHA)-loaded chitosan/alginate (CA) nanoparticles (NPs) developed by ionotropic gelation method. The physicochemical analyses of the composite NPs were performed by scanning electron microscopy, Fourier transform infrared spectroscopy, zeta potential, X-ray diffraction, and atomic force microscopy. The encapsulation efficiency of AMX was increased to 76% by incorporating DHA, which resulted in a reduction in the particle size. The formed CA-DHA-AMX NPs effectively adhered to the bacteria and rat gastric mucosa. Their antibacterial properties were more potent than those of the single AMX and CA-DHA NPs as demonstrated by the in vivo assay. The composite NPs attained higher mucoadhesive potential during food intake than during fasting (p = 0.029). At 10 and 20 mg/kg AMX, the CA-AMX-DHA showed more potent activities against H. pylori than the CA-AMX, CA-DHA, and single AMX. The in vivo study showed that the effective dose of AMX was lower when DHA was included, indicating better drug delivery and stability of the encapsulated AMX. Both mucosal thickening and ulcer index were significantly higher in the groups receiving CA-DHA-AMX than in the groups receiving CA-AMX and single AMX. The presence of DHA declines the pro-inflammatory cytokines including IL-1ß, IL-6, and IL-17A. The synergistic effects of AMX and the CA-DHA formulation increased the biocidal activities against H. pylori infection and improved ulcer healing properties.

Design of a dual-function agent by fusing a designed anti-VEGF-A binder and CPG-2 enzyme.

Anti-VEGF therapies are common for the treatment of cancer. Carboxypeptidase G (CPG-2) enzyme is a zinc-dependent metalloenzyme that metabolizes non-toxic synthetic 'benzoic mustard prodrugs' to cytotoxic moieties in tumor cells. In this study, we designed a dual-activity agent by combining a designed anti-VEGF- and CPG-2 enzyme to convert methotrexate (MTX). VEGF-A was docked against a set of scaffolds, and suitable inverse rotamers were made. Rosetta design was used for the interface design. The top 1200 binders were chosen by flow cytometry and displayed in yeast. The activity of CPG-2 enzyme was analyzed at different temperature conditions and in the presence of the substrate, MTX. Optimal binders were selected and protein was eluted using immobilized metal affinity chromatography and size-exclusion chromatography. Both, native PAGE and on-yeast flow cytometry confirmed the binding of the binder to VEGF-A. The activity of truncated enzymes was slightly lower than that of full-length enzymes linked to VEGF-A. The method should be generally useful as a dual-activity agent for targeting VEGF-A and combination therapy with the enzyme CPG-2 for metabolizing non-toxic prodrugs to cytotoxic moieties.Communicated by Ramaswamy H. Sarma.

Heterologous Prime-boost Vaccination Using Adenovirus and Albumin Nanoparticles as Carriers for Human Papillomavirus 16 E7 Epitope.

BACKGROUND: Nanocarriers are these days considered an attractive approach in cancer immunotherapy owing to their ability to deliver antigens to antigen-presenting cells (APCs) for stimulating robust immune cells against the tumor. OBJECTIVES: The objective of this study was to construct nanocomplexes using two nanocarriers with negative surface charge, adenovirus (Ad) and human serum albumin nanoparticle (HSA-NP), and coat their surface with a modified and positively-charged HPV16 E7 MHC-I specific epitope to assess their anti-tumor effects in a TC-1 mouse model. METHODS: After the construction of Ad and HSA-NP, their complexes with HPV16 E7 MHC-I specific epitope were characterized by zeta potential and dynamic light scattering. Then, the cellular immunity and CTL responses in immunized mice were assessed by measuring the levels of IL-10 and IFN-γ and the expression of CD107a, a marker of CTL response, as well as tumor inhibition. RESULTS: The zeta potential and dynamic light scattering results showed that incubation of the oppositely- charged nanocarriers and MHC-I specific epitope led to the formation of nanocomplexes in which the surface charge of nanocarriers was changed from negative to positive with minimal changes in the particle size. We demonstrated that the nanocomplex platforms in heterologous primeboost regimens generate significantly higher E7-specific IL-10, IFN-γ, and CTL responses. Moreover, the heterologous nanocomplex regimens, Alb/Pep-Ad/Pep and Ad/Pep-Alb/Pep, significantly suppressed the growth of TC-1 tumors in vivo compared with mice receiving homologous regimens and naked nanocarriers. CONCLUSION: The heterologous nanocomplexes might serve as an effective vaccine strategy against HPV-induced cervical cancer.

HNF4α is possibly the missing link between epithelial-mesenchymal transition and Warburg effect during hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is a heterogeneous, late-diagnosed, and highly recurrent malignancy that often affects the whole body's metabolism. Finding certain theranostic molecules that can address current concerns simultaneously is one of the priorities in HCC management. In this study, performing protein-protein interaction network analysis proposed hepatocyte nuclear factor 4 alpha (HNF4α) as a hub protein, associating epithelial-mesenchymal transition (EMT) to reprogrammed cancer metabolism, formerly known as the Warburg effect. Both phenomena improved the compensation of cancerous cells in competitive conditions. Mounting evidence has demonstrated that HNF4α is commonly downregulated and serves as a tumor suppressor in the HCC. Enhancing the HNF4α mRNA translation through a specific synthetic antisense long non-coding RNA, profoundly affects both EMT and onco-metabolic modules in HCC cells. HNF4α overexpression decreased featured mesenchymal transcription factors and improved hepatocytic function, decelerated glycolysis, accelerated gluconeogenesis, and improved dysregulated cholesterol metabolism. Moreover, HNF4α overexpression inhibited the migration, invasion, and proliferation of HCC cells and decreased metastasis rate and tumor growth in xenografted nude mice. Our findings suggest a central regulatory role for HNF4α through its broad access to a wide variety of gene promoters involved in EMT and the Warburg effect in human hepatocytes. This essential impact indicates that HNF4α may be a potential target for HCC treatment.

Antibacterial and Immunoregulatory Effects of Metformin against Helicobacter pylori Infection in Rat Model.

Introduction: Helicobacter pylori (H. pylori) induces gastritis by stimulating Th17 cells and related cytokines. The aim of our study was to investigate the synergistic effect of metformin with amoxicillin as an antibiotic in inhibiting H. pylori and modulating the immune response in a rat model. Methods: Forty-five male Sprague-Dawley rats were divided into seven groups and infected with H. pylori. Over the course of 14 days, all animals were treated with metformin and amoxicillin alone and in combination. The antibacterial activity of metformin was evaluated by growth curves and colony counts. The immunoregulatory effect on Treg/Th17 balance was assessed by flow cytometry, and the cytokine profile of IL-17A, IL-1ß, IL-6, IL-8, TGF-ß, and IL-10 was determined by ELISA. The effect of metformin on gene expression of cagA and IL-8 was investigated by RT-PCR. Pathological changes were assessed by hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining. Results: Metformin showed weak antibacterial activity against clinically isolated H. pylori. However, the combination of metformin and amoxicillin (AMX) showed strong synergistic antibacterial activity (ΣFIC = 0.24). Compared with AMX, metformin reduced inflammation and tissue damage but resulted in increased bacterial growth. During metformin administration, both TGF-ß levels and Treg cells increased dramatically (P = 0.002). In synergy with AMX, metformin decreased the effective dose of antibiotic to eradicate H. pylori. Conclusions: The combination of metformin with potential antibiotics such as AMX had a positive effect on the relief of H. pylori-related inflammation by inducing Treg cells while successfully eliminating H. pylori.

Bacteria-derived chimeric toxins as potential anticancer agents.

Cancer is one of the major causes of death globally, requiring everlasting efforts to develop novel, specific, effective, and safe treatment strategies. Despite advances in recent years, chemotherapy, as the primary treatment for cancer, still faces limitations such as the lack of specificity, drug resistance, and treatment failure. Bacterial toxins have great potential to be used as anticancer agents and can boost the effectiveness of cancer chemotherapeutics. Bacterial toxins exert anticancer effects by affecting the cell cycle and apoptotic pathways and regulating tumorigenesis. Chimeric toxins, which are recombinant derivatives of bacterial toxins, have been developed to address the low specificity of their conventional peers. Through their targeting moieties, chimeric toxins can specifically and effectively detect and kill cancer cells. This review takes a comprehensive look at the anticancer properties of bacteria-derived toxins and discusses their potential applications as therapeutic options for integrative cancer treatment.

Hepatogenesis and hepatocarcinogenesis: Alignment of the main signaling pathways.

Development is a symphony of cells differentiation in which different signaling pathways are orchestrated at specific times and periods to form mature and functional cells from undifferentiated cells. The similarity of the gene expression profile in malignant and undifferentiated cells is an interesting topic that has been proposed for many years and gave rise to the differentiation-therapy concept, which appears a rational insight and should be reconsidered. Hepatocellular carcinoma (HCC), as the sixth common cancer and the third leading cause of cancer death worldwide, is one of the health-threatening complications in communities where hepatotropic viruses are endemic. Sedentary lifestyle and high intake of calories are other risk factors. HCC is a complex condition in which various dimensions must be addressed, including heterogeneity of cells in the tumor mass, high invasiveness, and underlying diseases that limit the treatment options. Under these restrictions, recognizing, and targeting common signaling pathways during liver development and HCC could expedite to a rational therapeutic approach, reprograming malignant cells to well-differentiated ones in a functional state. Accordingly, in this review, we highlighted the commonalities of signaling pathways in hepatogenesis and hepatocarcinogenesis, and comprised an update on the current status of targeting these pathways in laboratory studies and clinical trials.

Monoclonal Antibody Against Sortilin Induces Apoptosis in Human Breast Cancer Cells.

Background: Sortilin has an important role in various malignances and can be used as a promising target to eradicate cancer cells. Methods: In this study, the expression of sortilin in 4T1 and MDA-MB231 cell lines was evaluated by flow cytometry and immunocytochemistry. Apoptosis assay was also applied to evaluate apoptosis induction in 4T1 and MDA-MB231 cell lines. Results: Based on cell surface flow cytometry results, anti-sortilin (2D8-E3) mAb could recognize sortilin molecules in 79.2% and 90.3% of 4T1 and MDA-MB231 cell-lines, respectively. The immunocytochemistry staining results confirmed sortilin surface expression. Apoptosis assay indicated that anti-sortilin mAb could induce apoptosis in 4T1 and MDA-MB231 cell lines. Conclusion: Our study revealed the important role of surface sortilin in breast carcinoma cell survival and its possible application as a therapeutic agent in cancer targeted therapies.

Screening of candidate genes associated with high titer production of oncolytic measles virus based on systems biology approach.

The number of viral particles required for oncolytic activity of measles virus (MV) can be more than a million times greater than the reported amount for vaccination. The aim of the current study is to find potential genes and signaling pathways that may be involved in the high-titer production of MV. In this study, a systems biology approach was considered including collection of gene expression profiles from the Gene Expression Omnibus (GEO) database, obtaining differentially expressed genes (DEGs), performing gene ontology, functional enrichment analyses, and topological analyses on the protein-protein interaction (PPI) network. Then, to validate the in-silico data, total RNA was isolated from five cell lines, and full-length cDNA from template RNA was synthesized. Subsequently, quantitative reverse transcription-PCR (RT-qPCR) was employed. We identified five hub genes, including RAC1, HSP90AA1, DNM1, LTBP1, and FSTL1 associated with the enhancement in MV titer. Pathway analysis indicated enrichment in PI3K-Akt signaling pathway, axon guidance, proteoglycans in cancer, regulation of actin cytoskeleton, focal adhesion, and calcium signaling pathways. Upon verification by RT-qPCR, the relative expression of candidate genes was generally consistent with our bioinformatics analysis. Hub genes and signaling pathways may be involved in understanding the pathological mechanisms by which measles virus manipulates host factors in order to facilitate its replication. RAC1, HSP90AA1, DNM1, LTBP1, and FSTL1 genes, in combination with genetic engineering techniques, will allow the direct design of high-throughput cell lines to answer the required amounts for the oncolytic activity of MV.

Exosomal microRNAs and long noncoding RNAs: Novel mediators of drug resistance in lung cancer.

Lung cancer therapeutic resistance, especially chemoresistance, is a key issue in the management of this malignancy. Despite the development of novel molecularly targeted drugs to promote therapeutic efficacy, 5-year survival of lung cancer patients is still dismal. Molecular studies through the recent years have fortunately presented multiple genes and signaling pathways, which contribute to lung cancer chemoresistance, providing a better perception of the biology of tumor cells, as well as the molecular mechanisms involved in their resistance to chemotherapeutic agents. Among those mechanisms, transfer of extracellular vesicles, such as exosomes, between cancer cells and the surrounding noncancerous ones is considered as an emerging route. Exosomes can desirably function as signaling vesicles to transmit multiple molecules from normal cells to cancer cells and their microenvironment, or vice versa. Using this ability, exosomes may affect the cancer cells' chemoresistance/chemosensitivity. Recently, noncoding RNAs (esp. microRNAs and long noncoding RNAs), as key molecules transferred by exosomes, have been reported to play a substantial role in the process of drug resistance, through modulation of various proteins and their corresponding genes. Accordingly, the current review principally aims to highlight exosomal micro- and long noncoding RNAs involved in lung cancer chemoresistance. Moreover, major molecular mechanisms, which connect corresponding RNA molecules to drug resistance, will briefly be addressed, for better clarifying of possible roles of exosomal noncoding RNAs in promoting the effectiveness of lung cancer therapy.

Vitamin D receptor gene polymorphisms and risk of breast cancer in Iranian women.

OBJECTIVES: Vitamin D deficiency is a driving force of common cancers like breast cancer. Vitamin D receptor (VDR) can play a tumor suppressor role by helping the precise function of vitamin D in cells such as modulation TGF-ß signaling pathway. This study aimed to investigate the association of VDR gene variants and susceptibility to breast cancer in Iranian women. METHODS: Genomic DNAs were isolated from blood samples of 161 women with breast cancer and 150 healthy women. After amplification of five positions of VDR gene, the prepared amplicons were digested with TaqI, ApaI, BsmI, Cdx2, and FokI restriction enzymes. RESULTS: Subsequently, the digested products were electrophoresed on the 1.5% agarose gel. Odds ratios (ORs) for breast cancer were calculated for genotypes and estimated haplotypes. Binary logistic regression analysis showed FokI (rs2228570), BsmI (rs1544410), and ApaI (rs7975232) polymorphisms had the significant distribution in patients than to the normal group. Analysis of linkage disequilibrium for all pairs of SNPs showed that D'-value between SNP TaqI and SNP BsmI was significantly (p ≤ 0.05). We observed that four major haplotypes of ApaI, BsmI, FokI, Cdx2, and TaqI SNPs significantly were in high frequency than predicted frequency. Among these four haplotypes, CGTAT haplotype was in a higher significant association than others with breast cancer risk (p-value = 0.0001). CONCLUSION: Our results showed that FokI, BsmI, and ApaI of VDR polymorphisms associated with the risk of breast cancer in Iranian population.