Advanced therapeutic modalities in hepatocellular carcinoma: Novel insights.

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is usually a latent and asymptomatic malignancy caused by different aetiologies, which is a result of various aberrant molecular heterogeneity and often diagnosed at advanced stages. The incidence and prevalence have significantly increased because of sedentary lifestyle, diabetes, chronic infection with hepatotropic viruses and exposure to aflatoxins. Due to advanced intra- or extrahepatic metastasis, recurrence is very common even after radical resection. In this paper, we highlighted novel therapeutic modalities, such as molecular-targeted therapies, targeted radionuclide therapies and epigenetic modification-based therapies. These topics are trending headlines and their combination with cell-based immunotherapies, and gene therapy has provided promising prospects for the future of HCC treatment. Moreover, a comprehensive overview of current and advanced therapeutic approaches is discussed and the advantages and limitations of each strategy are described. Finally, very recent and approved novel combined therapies and their promising results in HCC treatment have been introduced

Oncolytic adenovirus: A tool for cancer therapy in combination with other therapeutic approaches

Cancer therapy using oncolytic viruses is an emerging area, in which viruses are engineered to selectively propagate in tumor tissues without affecting healthy cells. Because of the advantages that adenoviruses (Ads) have over other viruses, they are more considered. To achieve tumor selectivity, two main modifications on Ads genome have been applied: small deletions and insertion of tissue- or tumor-specific promoters. Despite oncolytic adenoviruses ability in tumor cell lysis and immune responses stimulation, to further increase their antitumor effects, genomic modifications have been carried out including insertion of checkpoint inhibitors and antigenic or immunostimulatory molecules into the adenovirus genome and combination with dendritic cells and chemotherapeutic agents. This study reviews oncolytic adenoviruses structures, their antitumor efficacy in combination with other therapeutic strategies, and finally challenges around this treatment approach. © 2018 Wiley Periodicals, Inc

Monogenic Primary Immunodeficiency Disorder Associated with Common Variable Immunodeficiency and Autoimmunity

Background: Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency disorder mainly characterized by recurrent bacterial infections besides other immunological defects including loss of or dysfunction of B cells and decreased immunoglobulin levels. In this study, our aim is to evaluate clinical, immunological, and molecular data of patients with a primary clinical diagnosis of CVID and autoimmune phenotype with a confirmed genetic diagnosis. Methods: Among 297 patients with CVID, who were registered in the Iranian Primary Immunodeficiency Registry at Children's Medical Center Hospital in Iran, 83 patients have been genetically examined and 27 patients with autoimmunity and confirmed genetic mutations were selected for analysis. Whole-exome sequencing and confirmatory Sanger sequencing methods were used for the study population. A questionnaire was retrospectively filled for all patients to evaluate demographic, laboratory, clinical, and genetic data. Results: In the 27 studied patients, 11 different genetic defects were identified, and the most common mutated gene was LRBA, reported in 17 (63.0) patients. Two patients (7.7) showed autoimmune complications as the first presentation of immunodeficiency. Eleven patients (40.7) developed one type of autoimmunity, and 16 patients (59.3) progressed to poly-autoimmunity. Most of the patients with mono-autoimmunity (n = 9, 90.0) primarily developed infectious complications, while in patients with poly-autoimmunity, the most common first presentation was enteropathy (n = 6, 37.6). In 13 patients (61.9), the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency. The most frequent autoimmune manifestations were hematologic (40.7), gastrointestinal (48.1), rheumatologic (25.9), and dermatologic (22.2) disorders. Patients with poly-autoimmunity had lower regulatory T cells than patients with mono-autoimmunity. Conclusion: In our cohort, the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency in most patients. This association highlights the fact that patients referring with autoimmune manifestations should be evaluated for humoral immunity. © 2020 Georg Thieme Verlag. All rights reserved

Clinical and diagnostic potential of regulatory T cell markers: From bench to bedside

Regulatory T (Treg) cells are heterogeneous immune cell populations residing in the thymus and peripheral lymphatic tissues. This immune cell plays a central and critical role in maintaining immune tolerance against undesirable immune responses. Treg cells' phenotypic heterogeneity caused by different pathological conditions makes their identification and differentiation from non-suppressive T cells difficult. On the other hand, using nonspecific markers and variable isolation panels leads to undesirable outcomes. There are a variety of markers to identify functional Treg cells, including CD25, FOXP3, and CTLA-4, as well as the epigenetic signature of forkhead box P3 (FOXP3), which can be used for both natural and induced Treg cells. Phenotypic heterogeneity is a major concern in Treg purification when using nonspecific markers, which can be addressed by utilizing suitable isolation panels designed for different purposes. This review presents a clinical framework for Treg detection and isolation, focusing on Treg markers such as CD25, FOXP3, CTLA-4, CD127, GPA-33, and TSDR demethylation to design Treg isolation panels suitable for different Treg therapy purposes. The current review also highlights new reliable Treg markers applicable for different purposes

Fracture Toughness Evaluation of Hybrid and Nano-hybrid Resin Composites after Ageing under Acidic Environment

Statement of Problem: Tooth-coloured restorative materials are brittle with the major shortcomings of sensitivity to flaws and defects. Although various mechanical properties of resin composites have been studied, no fracture toughness test data for nano-hybrid composites under acidic condition for a long period of time has been published. Objectives: To compare the fracture toughness (KIc) of two types of resin composites under tensile loading and to assess the effect of distilled water and lactic acid on the resistance of the restoratives to fracture after three months of immersion. Materials and Methods: Four resin composites were used: three nanohybrids [EsteliteSigma Quick (Kuraray), Luna (SDI), Paradigm (3M/ESPE)] and one hybrid, Rok (SDI). The specimens were prepared using a custom-made polytetrafluorethylene split mould, stored in distilled water (pH 6.8) or 0.01mol/L lactic acid (pH 4) and conditioned at 37°C for 24 hours, 1 or 3 months. They were loaded under tensile stress using a universal testing machine; the maximum load (N) to the specimen failure was recorded and the fracture toughness (KIc) was calculated. Data were analysed by ANOVA and Tukey’s test using SPSS, version 18. Results: The results of two-way ANOVA did not show a significant combined effect of material, time, and storage medium on fracture toughness (p= 0.056). However, there was a strong interaction between materials and time (p=0.001) when the storage medium were ignored. After 24 h of immersion in distilled water, Paradigm revealed the highest KIc values followed by Rok, Luna and Estelite. Immersion in either distilled water or lactic acid significantly decreased the fracture toughness of almost all materials as time interval increased. Conclusions: Paradigm showed the highest fracture toughness followed by Rok, Luna and Estelite respectively. As time increased, KIc significantly decreased for almost all resin composites except for Luna which showed a slight decrease after one month of immersion in distilled water

Look Different: Effect of Radiation Hormesis on the Survival Rate of Immunosuppressed Mice

Background: Hormesis is defined as the bio-positive response of something which is bio-negative in high doses. In the present study, the effect of radiation hormesis was evaluated on the survival rate of immunosuppressed BALB/c mice by Cyclosporine A. Material and Methods: We used 75 consanguine, male, BALB/c mice in this experiment. The first group received Technetium-99m (3700Bq) and the second group was placed on a sample radioactive soil of Ramsar region (800Bq) for 20 days. The third group was exposed to X-rays (3600Bq) and the fourth group was placed on the radioactive soil and then injected Technetium-99m. The last group was the sham irradiated control group. Finally, 30mg Cyclosporine A as the immunosuppressive agent was orally administered to all mice 48 hours after receiving X-rays and Technetium99m. The mean survival rate of mice in each group was estimated during time. Results: A log rank test was run to determine if there were differences in the survival distribution for different groups and related treatments. According to the results, the survival rate of all pre-irradiated groups was more than the sham irradiated control group (p < .05). The highest survival time was related to the mice which were placed on the radioactive soil of Ramsar region for 20 days and then injected Technetium99m. Conclusion: This study confirmed the presence of hormetic models and the enhancement of survival rate in immunosuppressed BALB/c mice as a consequence of low-dose irradiation. It is also revealed the positive synergetic radioadaptive response on survival rate of immunosuppressed animals

Helicobacter pylori antibiotic resistance and correlation with cagA motifs and homB gene

Objectives: Helicobacter pylori (H. pylori) infection caused by antibiotic-resistant strains represents a major public health threat that aggressively promotes gastric cancer progression. Antibiotic resistance evaluation is immensely important to counteract its emergence. Here we merely determine the prevalence of antibiotic resistance in H. pylori isolates and its correlation with cagA motifs and the homB gene. Methods: The antibiotic resistance pattern was investigated on 128 H. pylori isolated strains utilizing the disk diffusion method and study the correlation between it and the presence of pathogenic genes, cagA EPIYA motifs and homB gene, were accurately detected using the PCR. Results: The resistance rates to four antibiotics were 70.1 for metronidazole, 35.5 for amoxicillin, 7.2 for clarithromycin and 8.2 for tetracycline. Resistance phenotypes were separated into two groups, single resistance (63.2) and multi-resistance (12.5). The prevalence of cagA-ABCC resistant strains and homB(+) resistant strains was significantly higher in cancer (p = 0.04 and p = 0.01, respectively) than those of other diseases. The prevalence of cagA-homB(+) resistance strains was 21.8 and had a significant correlation with PUD. A significant relationship was observed between amoxicillin resistant rate with ABC-homB (p = 0.0006). Conclusion: The Resistance rate to selected antibiotics in Shiraz is higher than years ago. The presence of cagA-homB(+) is associated with antibiotic resistance and also homB can be used as a marker to antibiotic resistance status prediction in H. pylori isolated in this area

Stem Cell Therapy: A New Therapeutic Option for Cardiovascular Diseases

Cardiovascular diseases are known as one of major causes of morbidity and mortality worldwide. Despite the many advancement in therapies are associated with cardiovascular diseases, it seems that finding of new therapeutic option is necessary. Cell therapy is one of attractive therapeutic platforms for treatment of a variety of diseases such as cardiovascular diseases. Among of various types of cell therapy, stem cell therapy has been emerged as an effective therapeutic approach in this area. Stem cells divided into multipotent stem cells and pluripotent stem cells. A large number studies indicated that utilization of each of them are associated with a variety of advantages and disadvantages. Multiple lines evidence indicated that stem cell therapy could be used as suitable therapeutic approach for treatment of cardiovascular diseases. Many clinical trials have been performed for assessing efficiency of stem cell therapies in human. However, stem cell therapy are associated with some challenges, but, it seems resolving of them could contribute to using of them as effective therapeutic approach for patients who suffering from cardiovascular diseases. In the current review, we summarized current therapeutic strategies based on stem cells for cardiovascular diseases. J. Cell. Biochem. 119: 95�104, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc

Directed differentiation of regulatory T cells from naive T cells and prevention of their inflammation-mediated instability using small molecules

Regulatory T (T-reg) cell therapy is a promising approach for immune tolerance induction in autoimmunity conditions and cell/organ transplantations. Insufficient isolation yields and impurity during downstream processes and T-reg instability after adoptive transfer in inflammatory conditions are major limitations to T-reg therapy, and indicate the importance of seeking a valid, reliable method for de-novo generation of T-regs. In this research, we evaluated T-reg-like cells obtained from different T-reg differentiation protocols in terms of their yield, purity and activity. Differentiation was performed on naive CD4(+) cells and a naive CD4(+)/T-reg co-culture by using three different protocols - ectopic expression of forkhead box protein P3 (E-FoxP3), soluble transforming growth factor beta (S-TGF) and small molecules N-acetyl puromycin and SR1555 (N-Ac/SR). The results showed that a high yield of a homogeneous population of T-reg-like cells could be achieved by the N-Ac/SR method under a T helper type 17 (Th17)-polarizing condition, particularly interleukin (IL)-6 and TGF-beta, when compared with the E-FoxP3 and S-TGF methods. Surprisingly, SR completely inhibited the differentiation of IL-17-producing cells and facilitated T-reg generation in the inflammatory condition and had highly suppressive activity against T cell proliferation without T-reg-specific demethylase region (TSDR) demethylation. For the first time, to our knowledge, we report the generation of efficient, pure T-reg-like cells by using small molecules during in-vitro inflammatory conditions. Our results suggested that the N-Ac/SR method has several advantages for T-reg generation when compared with the other methods, including a higher purity of T-regs, easier procedure, superior suppressive activity during the inflammatory condition and decreased cost