Recent Advances on Immune Targeted Therapy of Colorectal Cancer Using bi-Specific Antibodies and Therapeutic Vaccines.

Colorectal cancer (CRC) is a universal heterogeneous disease that is characterized by genetic and epigenetic alterations. Immunotherapy using monoclonal antibodies (mAb) and cancer vaccines are substitute strategies for CRC treatment. When cancer immunotherapy is combined with chemotherapy, surgery, and radiotherapy, the CRC treatment would become excessively efficient. One of the compelling immunotherapy approaches to increase the efficiency of CRC therapy is the deployment of therapeutic mAbs, nanobodies, bi-specific antibodies and cancer vaccines, which improve clinical outcomes in patients. Also, among the possible therapeutic approaches for CRC patients, gene vaccines in combination with antibodies are recently introduced as a new perspective. Here, we aimed to present the current progress in CRC immunotherapy, especially using Bi-specific antibodies and dendritic cells mRNA vaccines. For this aim, all data were extracted from Google Scholar, PubMed, Scopus, and Elsevier, using keywords cancer vaccines; CRC immunotherapy and CRC mRNA vaccines. About 97 articles were selected and investigated completely based on the latest developments and novelties on bi-specific antibodies, mRNA vaccines, nanobodies, and MGD007.

Long non-coding RNAs as potential biomarkers in the prognosis and diagnosis of lung cancer: A review and target analysis.

Long non-coding RNAs (lncRNA) have been emerged as a novel class of molecular regulators in cancer. They are dysregulated in many types of cancer; however, there is not enough knowledge available on their expression and functional profiles. Lung cancer is the leading cause of the cancer deaths worldwide. Generally, lncRNAs may be associated with lung tumor pathogenesis and they may act as biomarkers for the cancer prognosis and diagnosis. Compared to other invasive prognostic and diagnostic methods, detection of lncRNAs might be a user-friendly and noninvasive method. In this review article, we selected 27 tumor-associated lncRNAs by literature reviewing to further discussing in detail for using as diagnostic and prognostic biomarkers in lung cancer. Also, in an in silico target analysis, the "Experimentally supported functional regulation" approach of the LncTarD web tool was used to identifying the target genes and regulatory mechanisms of the selected lncRNAs. The reports on diagnostic and prognostic potential of all selected lncRNAs were discussed. However, the target genes and regulatory mechanisms of the 22 lncRNAs were identified by in silico analysis and we found the pathways that are controlled by each target group of lncRNAs. They use epigenetic mechanisms, ceRNA mechanisms, protein interaction and sponge mechanism. Also, 10, 23, 5, and 28 target genes for each of these mechanisms were identified, respectively. Finally, each group of target genes controls 50, 12, 7, and 2 molecular pathways, respectively. In conclusion, LncRNAs could be used as biomarkers in lung cancer due to their roles in control of several signaling pathways related to lung tumors. Also, it seems that lncRNAs, which use epigenetic mechanisms for modulating a large number of pathways, could be considered as important subjects for lung cancer-related diagnostic and prognostic biomarkers.

Colorectal cancer treatment using bacteria: focus on molecular mechanisms.

BACKGROUND: Colorectal cancer which is related to genetic and environmental risk factors, is among the most prevalent life-threatening cancers. Although several pathogenic bacteria are associated with colorectal cancer etiology, some others are considered as highly selective therapeutic agents in colorectal cancer. Nowadays, researchers are concentrating on bacteriotherapy as a novel effective therapeutic method with fewer or no side effects to pay the way of cancer therapy. The introduction of advanced and successful strategies in bacterial colorectal cancer therapy could be useful to identify new promising treatment strategies for colorectal cancer patients. MAIN TEXT: In this article, we scrutinized the beneficial effects of bacterial therapy in colorectal cancer amelioration focusing on different strategies to use a complete bacterial cell or bacterial-related biotherapeutics including toxins, bacteriocins, and other bacterial peptides and proteins. In addition, the utilization of bacteria as carriers for gene delivery or other known active ingredients in colorectal cancer therapy are reviewed and ultimately, the molecular mechanisms targeted by the bacterial treatment in the colorectal cancer tumors are detailed. CONCLUSIONS: Application of the bacterial instrument in cancer treatment is on its way through becoming a promising method of colorectal cancer targeted therapy with numerous successful studies and may someday be a practical strategy for cancer treatment, particularly colorectal cancer.

Critical roles of microRNA-196 in normal physiology and non-malignant diseases: Diagnostic and therapeutic implications.

MicroRNAs (miRNAs) have emerged as a critical component of regulatory networks that modulate and fine-tune gene expression in a post-transcriptional manner. The microRNA-196 family is encoded by three loci in the human genome, namely hsa-mir-196a-1, hsa-mir-196a-2, and hsa-mir-196b. Increasing evidence supports the roles of different components of this miRNA family in regulating key cellular processes during differentiation and development, ranging from inflammation and differentiation of stem cells to limb development and remodeling and structure of adipose tissue. This review first discusses about the genomic context and regulation of this miRNA family and then take a bird's eye view on the updated list of its target genes and their biological processes to obtain insights about various functions played by members of the microRNA-196 family. We then describe evidence supporting the involvement of the human microRNA-196 family in regulating critical cellular processes both in physiological and non-malignant inflammatory conditions, highlighting recent seminal findings that carry implications for developing novel therapeutic or diagnostic strategies.

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.

The oncogenic roles of bacterial infections in development of cancer.

Initiation of cancer is interconnected with different factors like infections. It has been estimated that infections, particularly viruses, participate in about 20% of all cancers. Bacteria as the most common infectious agents are also reported to be emerging players in the establishment of malignant cells. Microbial infections are able to modulate host cell transformation for promoting malignant features through the production of carcinogenic metabolites participating in inflammation responses, disruption of cell metabolism, and integrity and also genomic or epigenetic manipulations. It seems that the best example of the role of bacteria in cancer promotion is Helicobacter pylori infection, which is related to gastric cancer. World Health Organization (WHO) describes bacterium as class I carcinogens. Several bacterial infections have been reported in association with prevalent cancers. In this review, we will summarize the role of known bacterial infections in the initiation of the main common cancers, which show high mortality in the world. Examining the microbiomes in cancer patients is important and necessary to better understand the pathogenesis of this disease and also to plan therapeutic interventions.

Synthesis and application of magnetic@layered double hydroxide as an anti-inflammatory drugs nanocarrier.

BACKGROUND: Magnetic nanocomposites with a core-shell nanostructure have huge applications in different sciences especially in the release of the drugs, because of their exclusive physical and chemical properties. In this research, magnetic@layered double hydroxide multicore@shell nanostructure was synthesized by the facile experiment and is used as novel drug nanocarrier. METHODS: Magnetic nanospheres were synthesized by a facile one-step solvothermal route, and then, layered double hydroxide nanoflakes were prepared on the magnetic nanospheres by coprecipitation experiment. The synthesized nanostructures were characterized by FTIR, XRD, SEM, VSM, and TEM, respectively. After intercalation with Ibuprofen and Diclofenac as anti-inflammatory drugs and using exchange anion experiment, the basal spacing of synthesized layered double hydroxides was compared with brucite nanosheets from 0.48 nm to 2.62 nm and 2.22 nm, respectively. RESULTS: The results indicated that Ibuprofen and Diclofenac were successfully intercalated into the interlay space of LDHs via bridging bidentate interaction. In addition, in-vitro drug release experiments in pH 7.4, phosphate-buffered saline (PBS) showed constant release profiles with Ibuprofen and Diclofenac as model drugs with different lipophilicity, water solubility, size, and steric effect. CONCLUSION: The Fe3O4@LDH-ibuprofen and Fe3O4@LDH-diclofenac had the advantage of the strong interaction between the carboxyl groups with higher trivalent cations by bridging bidentate, clarity, and high thermal stability. It is confirmed that Fe3O4@LDH multicore-shell nanostructure may have potential application for constant drug delivery.

Overview of CD24 as a new molecular marker in ovarian cancer.

Ovarian cancer (OC) is the fifth leading cause of cancer-related death among women. The high mortality rate is due to lack of early symptoms, late diagnosis, limited treatment options, and also emerging of drug resistance. Todays, molecular markers have become promising in tumor-targeted therapy. Several molecular markers have been known in OC immunotherapy. Identification of the specific molecular markers with prognostic significance is interested. CD24 is a small sialoglycoprotein which is localized in lipid rafts through its glycosylphosphatidylinositol (GPI) anchor. It has been reported that CD24 is overexpressed in many cancers including OC. Also, CD24 is identified as a cancer stem cell marker in OC. The CD24 expression is associated with the development, invasion, and metastasis of cancer cells. The exact role of CD24 in cancer cells is not clearly understood. Recently, CD24 has been identified as an independent prognostic marker of survival in patients with OC. In this study, we reviewed the molecular targets in OC immune-targeted therapy and also presented an overview of the new molecular marker CD24 and its association with the OC by reviewing the recent literature.

Antibody-drug therapeutic conjugates: Potential of antibody-siRNAs in cancer therapy.

Codelivery is a promising strategy of targeted delivery of cytotoxic drugs for eradicating tumor cells. This rapidly growing method of drug delivery uses a conjugate containing drug linked to a smart carrier. Both two parts usually have therapeutic properties on the tumor cells. Monoclonal antibodies and their derivatives, such as Fab, scFv, and bsAb due to targeting high potent have now been attractive candidates as drug targeting carrier systems. The success of some therapeutic agents like small interfering RNA (siRNA), a small noncoding RNAs, with having problems such as enzymatic degradation and rapid renal filtration need to an appropriate carrier. Therefore, the aim of this study is to review the recent enhancements in development of antibody drug conjugates (ADCs), especially antibody-siRNA conjugates (SRCs), its characterizations and mechanisms in innovative cancer therapy approaches.

Immune therapy of melanoma: Overview of therapeutic vaccines.

Melanoma is the most serious type of skin cancer which develops from the occurrence of genetic mutations in the melanocytes. Based on the features of melanoma tumors such as location, genetic profile and stage, there are several therapeutic strategies including surgery, chemotherapy, and radiotherapy. However, because of the appearance resistance mechanisms, the efficiency of these treatments strategies may be reduced. It has been demonstrated that therapeutic monoclonal antibodies can improve the efficiency of melanoma therapies. Recently, several mAbs, such as nivolumab, pembrolizumab, and ipilimumab, were approved for the immunotherapy of melanoma. The antibodies inhibit immune checkpoint receptors such as CTL4 and pd-1. Another therapeutic strategy for the treatment of melanoma is cancer vaccines, which improve clinical outcomes in patients. The combination therapy using antibodies and gene vaccine give us a new perspective in the treatment of melanoma patients. Herein, we present the recent progressions in the melanoma immunotherapy, especially dendritic cells mRNA vaccines by reviewing recent literature.

Transient induction of Cdk9 in the early stage of differentiation is critical for myogenesis.

Cdk9 is a serine-threonine protein kinase that has been recognized as a regulator of cardiac differentiation. Recently, we have reported that transient induction of Cdk9 using noncoding RNA targeting Cdk9 sequences results in efficient cardiac differentiation. Concerning Cdk9 regulatory roles, here, we proposed whether constant overexpression of Cdk9 might influence the differentiation of myoblast C2C12 cells into myotubes. We overexpressed Cdk9 in mouse myoblast C2C12 cells to investigate its regulatory roles on myogenic differentiation. Upon Cdk9 overexpression, the expression level of myogenic regulatory factors was determined. Moreover, the expression profile of three important myomiRs consist of miR 1, 133 and 206 was examined during the differentiation process. Although Cdk9 expression is necessary for inducing differentiation in the early stage of myogenesis, continuous Cdk9 expression inhibits differentiation by modulating myomiRs and myogenic gene expression. Our results indicate that the transient induction of Cdk9 in the early stage of differentiation is critical for myogenesis.

Dysregulated expression of STAT1, miR-150, and miR-223 in peripheral blood mononuclear cells of coronary artery disease patients with significant or insignificant stenosis.

Coronary artery disease (CAD) is a multicellular disease characterized by chronic inflammation. Peripheral blood-mononuclear cells (PBMCs), as a critical component of immune system, actively cross-talk with pathophysiological conditions induced by endothelial cell injury, reflecting in perturbed PBMC expression. STAT1 is believed to be relevant to CAD pathogenesis through regulating key inflammatory processes and modulating STAT1 expression play key roles in fine-tuning CAD-related inflammatory processes. This study evaluated PBMC expressions of STAT1, and its regulators (miR-150 and miR-223) in a cohort including 72 patients with CAD with significant ( ≥ 50%) stenosis, 30 patients with insignificant ( < 50%) coronary stenosis (ICAD), and 74 healthy controls, and assessed potential of PBMC expressions to discriminate between patients and controls. We designed quantitative real-time polymerase chain reaction (RT-qPCR) assays and identified stable reference genes for normalizing PBMC quantities of miR-150, miR-223, and STAT1 applying geNorm algorithm to six small RNAs and five mRNAs. There was no significant difference between CAD and ICAD patients regarding STAT1 expression. However, both groups of patients had higher levels of STAT1 than healthy controls. miR-150 and miR-223 were differently expressed across three groups of subjects and were downregulated in patients compared with healthy controls, with the lowest expression levels being observed in patients with ICAD. ROC curves suggested that PBMC expressions may separate between different groups of study subjects. PBMC expressions also discriminated different clinical manifestations of CAD from ICADs or healthy controls. In conclusion, the present study reported PBMC dysregulations of STAT1, miR-150, and miR-223, in patients with significant or insignificant coronary stenosis and suggested that these changes may have diagnostic implications.

An overview on display systems (phage, bacterial, and yeast display) for production of anticancer antibodies; advantages and disadvantages.

Antibodies as ideal therapeutic and diagnostic molecules are among the top-selling drugs providing considerable efficacy in disease treatment, especially in cancer therapy. Limitations of the hybridoma technology as routine antibody generation method in conjunction with numerous developments in molecular biology led to the development of alternative approaches for the streamlined identification of most effective antibodies. In this regard, display selection technologies such as phage display, bacterial display, and yeast display have been widely promoted over the past three decades as ideal alternatives to traditional methods. The display of antibodies on phages is probably the most widespread of these methods, although surface display on bacteria or yeast have been employed successfully, as well. These methods using various sizes of combinatorial antibody libraries and different selection strategies possessing benefits in screening potency, generating, and isolation of high affinity antibodies with low risk of immunogenicity. Knowing the basics of each method assists in the design and retrieval process of antibodies suitable for different diseases, including cancer. In this review, we aim to outline the basics of each library construction and its display method, screening and selection steps. The advantages and disadvantages in comparison to alternative methods, and their applications in antibody engineering will be explained. Finally, we will review approved or non-approved therapeutic antibodies developed by employing these methods, which may serve as therapeutic antibodies in cancer therapy.

Recent Advances in Therapeutic Peptides for Breast Cancer Treatment.

Breast cancer is a heterogeneous malignancy and is the second leading cause of mortality among women around the world. Increasing the resistance to anti-cancer drugs in breast cancer cells persuades researchers to search the novel therapeutic approaches for the treatment of this malignancy. Among the novel methods, therapeutic peptides that target and disrupt tumor cells have been of great interest. Therapeutic peptides are short amino acid monomer chains with high specificity to bind and modulate a protein interaction of interest. Several advantages of peptides, such as specific binding on tumor cells surface, low molecular weight, and low toxicity on normal cells, make the peptides appealing therapeutic agents against solid tumors, particularly breast cancer. Also, the National Institutes of Health (NIH) describes therapeutic peptides as a suitable candidate for the treatment of drug-resistant breast cancer. In this review, we attempt to review the different therapeutic peptides against breast cancer cells that can be used in the treatment and diagnosis of the malignancy. Meanwhile, we presented an overview of peptide vaccines that have been developed for the treatment of breast cancer.

Evaluation of Mutations in 23S rRNA, rdxA and frxA Genes of Helicobacter pylori in Paraffin-Embedded Gastric Biopsy Specimens from Iranian Gastric Cancer and Gastritis Patients.

PURPOSE: Helicobacter pylori (H. pylori) infection is considered as one of the main cause of gastric cancer. Treatment failure of the infection often occurs due to antibiotic resistance. Herein, we aimed to evaluate the mutations in 23S rRNA gene of H. pylori which are associated with clarithromycin resistance and in rdxA and frxA genes of the bacterium which may be associated with metronidazole resistance, in paraffin-embedded gastric biopsies from patients with gastric adenocarcinoma and gastritis in Tabriz, the northwest of Iran. METHODS: In the study, 80 paraffin-embedded tissue sections from 40 gastric cancer and 40 gastritis patients in the Imam Reza hospital, Tabriz, Iran were collected. The existence of ureC gene was verified by PCR method. Genotypical clarithromycin resistance was investigated by real-time PCR method and determination of the melting temperature. PCR reaction and sequencing were used for the evaluation of mutations in rdxA and frxA genes. RESULTS: The results of ureC amplification showed that DNA of H. pylori was present in the 82.66% of the obtained DNA samples. About 45.16% of samples were resistant to the clarithromycin and 53.22% of them were resistant to the metronidazole. Based on the results from real-time PCR, the frequency of mutations was as follow A2143G 64.28%, A2142G 44.44% and A2142C 1.11%. The mutations of rdxA gene were 66.66% missense, 30.30% frameshift and 3.03% non-sense. The mutations of frxA gene were 36.36% missense, 54.54% frameshift and non-sense 9.09%. CONCLUSION: A2143G mutation is the most frequent mutation among clarithromycin resistant genes in Iran. Also, missense and frameshift mutations are frequent in rdxA and frxA genes. Screening for these mutations could help researchers to investigate the most effective anti-H. pylori antibiotics and to prevent antibiotic resistance.

Transplantation of Stem Cells as a Potential Therapeutic Strategy in Neurodegenerative Disorders.

Stem cells are considered to have significant capacity to differentiate into various cell types in humans and animals. Unlike specialized cells, these cells can proliferate several times to produce millions of cells. Nowadays, pluripotent stem cells are important candidates to provide a renewable source for the replacement of cells in tissues of interest. The damage to neurons and glial cells in the brain or spinal cord is present in neurological disorders such as Amyotrophic lateral sclerosis, stroke, Parkinson's disease, multiple sclerosis, Alzheimer's disease, Huntington's disease, spinal cord injury, lysosomal storage disorder, epilepsy, and glioblastoma. Therefore, stem cell transplantation can be used as a novel therapeutic approach in cases of brain and spinal cord damage. Recently, researchers have generated neuron-like cells and glial-like cells from embryonic stem cells, mesenchymal stem cells, and neural stem cells. In addition, several experimental studies have been performed for developing stem cell transplantation in brain tissue. Herein, we focus on stem cell therapy to regenerate injured tissue resulting from neurological diseases and then discuss possible differentiation pathways of stem cells to the renewal of neurons.

Recent developments in antibody derivatives against colorectal cancer; A review.

Colorectal cancer (CRC) is the fourth most common cause of cancer and mortality worldwide and is the third most common cancer in men and women. Surgery, radiotherapy, and chemotherapy are conventionally used for the treatment of colorectal cancer. However, these methods are associated with various side effects on normal cells. Thus, new studies are moving towards more effective and non-invasive methods for treatment of colorectal cancer. Targeted therapy of CRC is a promising new approach to enhance the efficiency and decrease the toxicity of the treatment. In targeted therapy of CRC, antibody fragments can directly inhibit tumor cell growth and proliferation. They also can act as an ideal carrier for targeted delivery of anticancer drugs. In the present study, the structure and function of different formats of antibody fragments, immune-targeted therapy of CRC using antibody fragments will be discussed.

The role of circadian genes in the pathogenesis of colorectal cancer.

Colorectal cancer (CRC) is the third most frequent cancer in human beings and is also the major cause of death among the other gastrointestinal cancers. The exact mechanisms of CRC development in most patients remains unclear. So far, several genetically, environmental and epigenetically risk factors have been identified for CRC development. The circadian rhythm is a 24-h rhythm that drives several biologic processes. The circadian system is guided by a central pacemaker which is located in the suprachiasmatic nucleus (SCN) in the hypothalamus. Circadian rhythm is regulated by circadian clock genes, cytokines and hormones like melatonin. Disruptions in biological rhythms are known to be strongly associated with several diseases, including cancer. The role of the different circadian genes has been verified in various cancers, however, the pathways of different circadian genes in the pathogenesis of CRC are less investigated. Identification of the details of the pathways in CRC helps researchers to explore new therapies for the malignancy.

Potential Roles of MyomiRs in Cardiac Development and Related Diseases.

Muscle-specific miRNAs, which are known as MyomiRs, are crucial regulatory elements for cardiovascular development. MyomiRs are abundantly expressed in the myocardium and regulate certain aspects of physiological and pathological processes in myocardiocytes, including cardiovascular development, myocardial remodeling, and arise for cardiovascular diseases through different mechanisms, such as epigenetic pathways. Clinical and experimental studies have confirmed the myomiRs as promising diagnostic biomarkers for the early diagnosis of cardiac disorders. In this review, we have summarized recent findings in the field of epigenetic modulations of myomiRs and cardiac regeneration associated with cardiac diseases.