Current therapeutic approaches and promising perspectives of using bioengineered peptides in fighting chemoresistance in triple-negative breast cancer.

Breast cancer is a collation of malignancies that manifest in the mammary glands at the early stages. Among breast cancer subtypes, triple-negative breast cancer (TNBC) shows the most aggressive behavior, with apparent stemness features. Owing to the lack of response to hormone therapy and specific targeted therapies, chemotherapy remains the first line of the TNBC treatment. However, the acquisition of resistance to chemotherapeutic agents increase therapy failure, and promotes cancer recurrence and distant metastasis. Invasive primary tumors are the birthplace of cancer burden, though metastasis is a key attribute of TNBC-associated morbidity and mortality. Targeting the chemoresistant metastases-initiating cells via specific therapeutic agents with affinity to the upregulated molecular targets is a promising step in the TNBC clinical management. Exploring the capacity of peptides as biocompatible entities with the specificity of action, low immunogenicity, and robust efficacy provides a principle for designing peptide-based drugs capable of increasing the efficacy of current chemotherapy agents for selective targeting of the drug-tolerant TNBC cells. Here, we first focus on the resistance mechanisms that TNBC cells acquire to evade the effect of chemotherapeutic agents. Next, the novel therapeutic approaches employing tumor-targeting peptides to exploit the mechanisms of drug resistance in chemorefractory TNBC are described.

Analysis of T cell repertoires of CD45RO CD4 T cells in cohorts of patients with bullous pemphigoid: A pilot study.

Autoimmune diseases develop over years - starting from a subclinical phenotype to clinically manifest autoimmune disease. The factors that drive this transition are ill-defined. To predict the turning point towards clinical disease and to intervene in the progress of autoimmune-mediated dysfunction, the establishment of new biomarkers is needed. Especially CD4 T cells are crucially involved in autoimmunity: first, during the initiation phase, because they lose their tolerance towards self-peptides, and second, by the subsequent ongoing presentation of self-peptides during the active autoimmune disease. Accordingly, changes in the degree of diversity of T cell receptor (TCR) repertoires in autoimmunity have been reported. These findings led to the hypothesis that transition from pre-disease to autoimmune disease is associated with an increase of abnormally expanded T cell clones that occupy large portions of the TCR repertoire. In this pilot study, we asked whether the ratio and the diversity of the TCR repertoires of circulating memory (CD45RO) and naïve (CD45RA) CD4 T cells could serve as a predictive factor for the development of autoimmunity. To find out, we analyzed the TCRß repertoires of memory and naïve CD4 T cells in a small cohort of four gender- and age-matched elderly patients having the autoimmune blistering disease bullous pemphigoid or non-melanoma skin cancers. We found that the extent of clonal expansions in the TCRß repertoires from the circulating memory and naïve CD4 populations did not differ between the patient groups. This result shows that the diversity of TCR repertoires from peripheral CD4 T cells does not reflect the manifestation of the skin-associated autoimmune disease BP and does not qualify as a prognostic factor. We propose that longitudinal TCR repertoire analysis of younger patients might be more informative.

Clinical whole-exome sequencing analysis reveals a novel missense COL11A1 mutation resulting in an 18-week Iranian male aborted fetus with Fibrochondrogenesis 1: A case report.

Fibrochondrogenesis 1, an autosomal recessive syndrome, is a rare disease that causes short-limbed skeletal dysplasia. Mutations in the gene encoding the α1 chain of type XI collagen (COL11A1) are seen to be the main cause of this disease. We present an 18-week Iranian male aborted fetus with Fibrochondrogenesis 1 from consanguineous parents. Whole-exome sequencing revealed a novel missense variant from G to A in exon 45 of 68 in the COL11A1 gene (NM_080629.2: c.3440G > A, [p.G1147E, g.103404625]). The mutation was confirmed by Sanger sequencing and further, MutationTaster predicted this variant to be disease-causing. Bioinformatic analysis suggests that this variant is highly conserved in both nucleotide and protein levels, suggesting that it has an important function in the proper role of COL11A1 protein. In silico analysis suggests that this mutation alters the COL11A1 protein structure through a Glycine to Glutamic acid substitution.

Protocol to Induce Follicular T Helper Cells, Germinal Centers, and Skin Lesions in Mouse Models for Skin Blistering Diseases.

Autoreactive T cells in autoantibody-mediated autoimmune diseases can be divided into two major subsets: (i) follicular T helper cells (Tfh) that provide T cell help in germinal centers (GC) and (ii) effector T (Teff) cells that immigrate into peripheral tissue sites such as the skin and mediate local inflammation. To study the sequence of events leading to the loss of tolerance in autoantibody-mediated autoimmune diseases it is required to investigate both T cell subsets simultaneously. This approach is hampered mainly because the appearance of skin inflammation in mouse models is a random process, which makes it difficult to define the location of inflammation at the right time point. To overcome this problem, we developed a scratching technique for ear skins that leads to the establishment of chronic autoimmune wounds in the mouse model for the pemphigoid-like disease epidermolysis bullosa acquisita. By defining the exact place where the skin wounds should form, this protocol enables a detailed analysis of skin-immigrating Teff cells. Of note, this protocol induces GC in draining lymph nodes in parallel so that Tfh cells in GC can be investigated concurrently. This protocol is not restricted to T cells and can be used for any other skin-immigrating inflammatory cells.

Protocol to Isolate Germinal Centers by Laser Microdissection.

During adaptive immune responses, germinal centers (GC) appear as transient microstructures, in which antigen-specific B and T cells interact with each other. Because only the antigen-activated B and T cells, such as Plasmablasts or follicular T helper (Tfh) cells, are present in GC, the in depth-analysis of GC is of great interest. To identify the cells that reside within GC, the majority of studies use the expression of specific surface molecules for analysis by flow cytometry. To do so, the tissue has to be disrupted for the preparation of single-cell suspensions. Thereby, the local information regarding neighborhoods of B cells and T cells and their potential interaction is lost. To study GC in vivo within their original microenvironment, we established a protocol for the isolation of GC by laser microdissection. To enable the identification of GC for subsequent transcriptomic analysis, the degradation of mRNA was diminished by using frozen tissues and by establishing a rapid staining protocol. This procedure enables histological and transcriptomic analysis of individual GC even within one lymphoid organ.

Gallium Components-Based Drug Delivery: A Potential Treatment for COVID-19.

With severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) showing new characteristics and manifesting new variants, the efficacy of vaccination can be reduced. In the meanwhile, no SARS-CoV-2-specific drug has been introduced in the fight against coronavirus disease 2019 (COVID-19) yet, and currently used drugs have also shown serious side effects in patients under treatment. Thus, it is pivotal to continue researching potential therapeutics to treat COVID-19. Recently, studies have shown that Gallium maltolate disrupts the replication of SARS-CoV-2 and therefore has antiviral activity against this virus. Nevertheless, as Gallium compounds have manifested serious side effects in the human body (e.g., hemoglobin synthesis dysfunction and pulmonary complications), drug delivery methods should be recruited to minimize the possible side effects and to optimize the efficacy of the drug in the fight against COVID-19. Liposomes, as nanocarriers, not only increase the half-life of the conjugated compound but also have shown promising features in the delivery of COVID-19-specific drugs to the target tissue. Herein, we propose that conjugation of Gallium maltolate with liposome nanocarriers can be beneficial to target tissues infected with SARS-CoV-2.

MicroRNAs and Diabetes Mellitus Type 1.

Type 1 diabetes mellitus is a multifactorial, progressive, autoimmune disease with a strong genetic feature that can affect multiple organs, including the kidney, eyes, and nerves. Early detection of type 1 diabetes can help critically to avoid serious damages to these organs. MicroRNAs are small RNA molecules that act in post-transcriptional gene regulation by attaching to the complementary sequence in the 3'-untranslated region of their target genes. Alterations in the expression of microRNA coding genes are extensively reported in several diseases, such as type 1 diabetes. Presenting non-invasive biomarkers for early detection of type 1 diabetes by quantifying microRNAs gene expression level can be a significant step in biotechnology and medicine. This review discusses the area of microRNAs dysregulation in type 1 diabetes and affected molecular mechanisms involved in pancreatic islet cell formation and dysregulation in the expression of inflammatory elements as well as pro-inflammatory cytokines.

The role of noncoding RNAs in pituitary adenoma.

Pituitary adenomas (PAs) are common cranial tumors that affect the quality of life in patients. Early detection of PA is beneficial for avoiding clinical complications of this disease and increasing the quality of life. Noncoding RNAs, including long noncoding RNA, miRNA and circRNA, regulate protein expression, mostly by inhibiting the translation process. Studies have shown that dysregulation of noncoding RNAs is associated with PA. Hence understanding the expression pattern of noncoding RNAs can be considered a promising method for developing biomarkers. This article reviews data on the expression pattern of dysregulated noncoding RNAs involved in PA. Possible molecular mechanisms by which the dysregulated noncoding RNA could possibly induce PA are also described.

Lay abstract Pituitary adenomas (PA) are benign, slow-growing tumors of the pituitary gland. The sooner the tumor is diagnosed, the sooner can the patient be treated with medication. The early detection of this disease can reduce the need for surgery to remove the tumor. Noncoding RNAs are small molecules that regulate the functions and behavior of different cells. When the intracellular or extracellular concentration of these small molecules is altered, the functions and behavior of cells and tissues can be affected and changed. Quantifying and analyzing these molecules is a promising tool for the early detection of different diseases, including PA. This article reviews alterations in these small molecules and the relationship between these alterations and the incidence of PA.

microRNA-related single-nucleotide polymorphisms and breast cancer.

Breast cancer, as the most common cancer in women which affects patients both mentally and physically, requires great attention in many areas and many levels as this cancer is known to be multifactorial. Single-stranded molecules called microRNAs with near 22 nucleotides are seen to act in central dogma of molecular biology by inhibiting the translation process; it is demonstrated that any alteration in their sequence especially single-nucleotide polymorphisms (SNPs) may lead into increasing the breast cancer risk. miR-SNPs are considered to be the potential biomarkers for early detection of breast cancer. As a result, this review documents the well-known miR-SNPs that are known to be associated with breast cancer. In this regard, two principals were discussed: (a) SNPs in the target genes of microRNAs and the alteration in gene expression due to this phenomenon; (b) changes based on the SNPs in the microRNA coding region and the impact on their interaction with target messenger RNA.

The role of angiotensin-converting enzyme 2 in COVID-19 induced lung injury.

The novel coronavirus disease (COVID-19) has affected people around the world both physically and psychologically. As result, developing coronavirus-specific vaccine and/or therapeutics is now a top priority for public health agencies. Since our findings about COVID-19 are relatively new, the current knowledge about the molecular mechanism involved in pathogenicity and virulence of the novel coronavirus is not advanced. Understanding angiotensin-converting enzyme 2 (ACE2), the receptor for the coronavirus, is significantly important. To better illustrate the role of ACE2 in the severity of COVID-19 and the impact of currently used drugs on this receptor, this paper briefly reviews newly published articles in this regard.