Raheleh Roudi is a research scientist in the Department of Radiology at Stanford University. Dr. Roudi trained at the Iran University of Medical Sciences, Iran. She worked as an Assistant Professor at the Iran University of Medical Sciences, Iran from 2015 to 2019, before coming to the United States. During this time, Dr. Roudi worked on several projects which have led to successful collaborations with the Karolinska Institute; Charite Universitatsmedizin Berlin; Oslo University Hospital; National University of Singapore; Shanghai University of Traditional Chinese Medicine and University of Brescia, among other internationally recognized institutions.
Dr. Roudi was a visiting scientist in the University of Texas at San Antonio and then appointed as a postdoctoral associate at the University of Minnesota for one year, before joining Stanford University in 2022.
Her research interest focuses on the molecular oncology and immunotherapies of solid tumors and she published more than 40 peer reviewed papers.
Immunotherapeutic treatments in hepatocellular carcinoma; achievements, challenges and future prospects.
2021; 101 (Pt A): 108322
Hepatocellular carcinoma (HCC) is one of the most common and fatal malignancies with an alarming trend all around the world. Common therapeutic approaches in the early stage of disease are surgical resection, ablation, and liver transplantation. Due to the insidious identity of HCC, the majority of the patients are diagnosed at advanced stages, where tumor spreading, or distant metastasis unfortunately have already occurred. Immunotherapeutic options have elicited a promising approach in some malignancies with Food and Drug Administration (FDA) approving the first checkpoint inhibitor anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ipilimumab for the treatment of melanoma ten years ago. In the past decade, many clinical trials have been investigating anti-CTLA-4 as well as anti-programmed cell death protein 1 (PD-1) therapies in various solid tumors, including HCC. In this mini-review we will discuss the latest clinical data from clinical trials for immune-checkpoint inhibitors for the treatment of HCC.
View details for DOI 10.1016/j.intimp.2021.108322
View details for PubMedID 34735916
p53 Antibodies as a Diagnostic Marker for Cancer: A Meta-Analysis.
Molecules (Basel, Switzerland)
2021; 26 (20)
Importance: The protein p53 is an unequivocal tumor suppressor that is altered in half of all cancers. The immune system produces systemic p53 autoantibodies (p53 Abs) in many cancer patients. Objective: This systemic review and meta-analysis focuses on the prognostic value of p53 Abs expressed in the serum of patients with solid tumors. Data Sources: All the clinical investigations were searched on PubMed from the first study dated 1993 until May 2021 (date of submission of the manuscript). Study Selection: Studies were included that met the following criteria: (1) participants with cancer; (2) outcome results expressed in relation to the presence of a p53 antibody; (3) a primary outcome (disease-free survival, overall survival or progression-free survival) expressed as hazard ratio (HR). The following exclusion criteria were used: (1) insufficient data available to evaluate outcomes; (2) animal studies; (3) studies with less than 10 participants. As a result, 12 studies were included in the analysis. Data Extraction and Synthesis: PRISMA guidelines were used for abstracting and assessing data quality and validity by three independent observers. The summary estimates were generated using a fixed-effect model (Mantel-Haenszel method) or a random-effect model (DerSimonian-Laird method), depending on the absence or presence of heterogeneity (I2). Main Outcome(s) and Measure(s): The primary study outcome was to determine the prognostic value of p53 Abs from a large population of patients with solid tumors, as determined before data collection. Results: In total, 12 clinical studies involving 2094 patients were included in the meta-analysis, and it was determined that p53 Abs expression in the serum significantly correlated with poorer survival outcomes of cancer patients (95% CI 1.48 [1.24, 1.77]; p < 0.00001). Conclusions and Relevance: This is the first meta-analysis proving the diagnostic utility of p53-Abs for cancer patients in predicting poorer outcomes. The serum-p53 value (s-p53-value) may be useful for future theranostics.
View details for DOI 10.3390/molecules26206215
View details for PubMedID 34684792
View details for PubMedCentralID PMC8541220
Immune checkpoint inhibitors and chemotherapy in first-line NSCLC: a meta-analysis.
2021; 13 (7): 621-631
This study is a meta-analysis of randomized controlled trials involving first-line studies in which immune checkpoint inhibitors were added to chemotherapy and were compared with chemotherapy alone. The primary end point was overall survival (OS). The analyses used random-effects models and the Grading of Recommendations Assessment, Development, and Evaluation system to rate the quality of the evidence. Nine articles were included for qualitative and quantitative synthesis. A meta-analysis of the nine randomized trials showed a significant benefit in terms of OS (hazard ratio: 0.75 [95% CI: 0.66-0.85]; p < 0.01). Only programmed death ligand-1 positive-high cancers derive a significant OS benefit. In this meta-analysis, there is moderate evidence that the addition of immune checkpoint inhibitors to chemotherapy may improve both OS compared with chemotherapy alone.
View details for DOI 10.2217/imt-2020-0224
View details for PubMedID 33775103
CTLA-4 in Regulatory T Cells for Cancer Immunotherapy.
2021; 13 (6)
Immune checkpoint inhibitors (ICIs) have obtained durable responses in many cancers, making it possible to foresee their potential in improving the health of cancer patients. However, immunotherapies are currently limited to a minority of patients and there is a need to develop a better understanding of the basic molecular mechanisms and functions of pivotal immune regulatory molecules. Immune checkpoint cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and regulatory T (Treg) cells play pivotal roles in hindering the anticancer immunity. Treg cells suppress antigen-presenting cells (APCs) by depleting immune stimulating cytokines, producing immunosuppressive cytokines and constitutively expressing CTLA-4. CTLA-4 molecules bind to CD80 and CD86 with a higher affinity than CD28 and act as competitive inhibitors of CD28 in APCs. The purpose of this review is to summarize state-of-the-art understanding of the molecular mechanisms underlining CTLA-4 immune regulation and the correlation of the ICI response with CTLA-4 expression in Treg cells from preclinical and clinical studies for possibly improving CTLA-4-based immunotherapies, while highlighting the knowledge gap.
View details for DOI 10.3390/cancers13061440
View details for PubMedID 33809974
View details for PubMedCentralID PMC8005092
- Immunotherapy‑based combinations versus standard first‑line and hypothyroidism risk. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 2020; 22 (9): 1664-1665
Expression patterns and clinical significance of the potential cancer stem cell markers OCT4 and NANOG in colorectal cancer patients.
Molecular & cellular oncology
2020; 7 (5): 1788366
Colorectal cancer (CRC) is one of the most important malignancies and causes of cancer-related deaths worldwide. Cancer stem cell markers identification could be helpful to acquire important prognostic information and develop new treatment regimens. This study aimed to evaluate the expression of OCT4 and NANOG in CRC patients and their clinical significance.Totally 359 CRC samples were stained for OCT4 and NANOG expression using tissue microarray. The correlation between their expression and clinical and pathological features was explored.The majority of CRC cases showed low-level expression of OCT4 (80%) and NANOG (75%). Lower expression of OCT4 was more often detected in CRC cases with no vascular involvement (P = .01). Also, a trend found between low level of OCT4 expression and absence of distant metastasis or lymph node involvement (P = .07 and P = .09, respectively). Surprisingly, a significant positive correlation was observed between NANOG expression and cellular differentiation (P = .05). Our combined analysis demonstrated that OCT4 low/NANOG low phenotype has frequently seen in colorectal cancer cases with no vascular invasion (P = .05).Our observations indicated that higher expression of OCT4 and NANOG can confer malignant and aggressive behavior to CRC. Evaluation of the co-expression of these cancer stem cell markers can serve a new diagnostic and prognostic approach in CRC patients. These findings also suggested that simultaneous expression of OCT4 and NANOG can be considered as a therapeutic marker for targeted therapy of CRC, especially in advanced stages.
View details for DOI 10.1080/23723556.2020.1788366
View details for PubMedID 32944642
View details for PubMedCentralID PMC7469450
Potential theranostics of circulating tumor cells and tumor-derived exosomes application in colorectal cancer.
Cancer cell international
2020; 20: 288
At the present time, colorectal cancer (CRC) is still known as a disease with a high mortality rate. Theranostics are flawless scenarios that link diagnosis with therapy, including precision medicine as a critical platform that relies on the development of biomarkers particularly "liquid biopsy". Circulating tumor cells (CTCs) and tumor-derived exosomes (TDEs) in a liquid biopsy approach are of substantial importance in comparison with traditional ones, which cannot generally be performed to determine the dynamics of the tumor due to its wide restriction of range. Thus, recent attempts has shifted towards minimally noninvasive methods.CTCs and TDEs, as significant signals emitted from the tumor microenvironment, which are also detectable in the blood, prove themselves to be promising novel biomarkers for cancer diagnosis, prognosis, and treatment response prediction. The therapeutic potential of them is still limited, and studies are at its infancy. One of the major challenges for the implementation of CTCs and TDEs which are new trends in translational medicine is the development of isolation and characterization; a standardizable approach. This review highlights and discusses the current challenges to find the bio fluids application in CRC early detection and clinical management.Taken together, CTCs and TDEs as silent drivers of metastasis can serve in the management of cancer patient treatment and it is of the upmost importance to expand our insight into this subject. However, due to the limited data available from clinical trials, further validations are required before addressing their putative application in oncology.
View details for DOI 10.1186/s12935-020-01389-3
View details for PubMedID 32655320
View details for PubMedCentralID PMC7339440
Dendritic cell/cytokine-induced killer cell-based immunotherapy in lung cancer: What we know and future landscape.
Journal of cellular physiology
2020; 235 (1): 74-86
Multiple modalities for lung cancer therapy have emerged in the past decade, whereas their clinical applications and survival-beneficiary is little known. Vaccination with dendritic cells (DCs) or DCs/cytokine-induced killer (CIK) cells has shown limited success in the treatment of patients with advanced non-small-cell lung cancer. To evaluate and overcome these limitations in further studies, in the present review, we sum up recent progress about DCs or DCs/CIKs-based approaches for preclinical and clinical trials in patients with lung cancer and discuss some of the limited therapeutic success. Moreover, this review highlights the need to focus future studies on the development of new approaches for successful immunotherapy in patients with lung cancer.
View details for DOI 10.1002/jcp.28977
View details for PubMedID 31222740
Spheroid-Derived Cells From Renal Adenocarcinoma Have Low Telomerase Activity and High Stem-Like and Invasive Characteristics.
Frontiers in oncology
2019; 9: 1302
Cancer stem cells (CSCs) are a theorized small subpopulation of cells within tumors thought to be responsible for metastasis, tumor development, disease progression, treatment-resistance, and recurrence. The identification, isolation, and biological characterization of CSCs may therefore facilitate the development of efficient therapeutic strategies targeting CSCs. This study aims to compare the biology and telomerase activity of CSCs to parental cells (PCs) in renal cancer. Renal CSCs were enriched from the ACHN cell line using a sphere culture system. Spheroid-derived cells (SDCs) and their adherent counterparts were compared with respect to their colony and sphere formation, expression of putative CSC markers, tumorigenicity in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, and invasiveness. The expression of genes associated with CSCs, stemness, EMT, apoptosis, and ABC transporters was also compared between the two populations using quantitative real-time PCR (qRT-PCR). Finally, telomerase activity, hTERT expression, and sensitivity to MST-312, a telomerase inhibitor, was investigated between the two populations. We demonstrated that a subpopulation of ACHN cells was capable of growing as spheroids with many properties similar to CSCs, including higher clonogenicity, superior colony- and sphere-forming ability, and stronger tumorigenicity and invasiveness. In addition, SDCs demonstrated a higher expression of markers for CSCs, stemness, EMT, apoptosis, and ABC transporter genes compared to PCs. The expression of hTERT and telomerase activity in SDCs was significantly lower than PCs; however, the SDC population was more sensitive to MST-312 compared to PCs. These findings indicate that the SDC population exhibits stem-like potential and invasive characteristics. Moreover, the reduced expression of hTERT and telomerase activity in SDCs demonstrated that the expressions of hTERT and telomerase activity are not always higher in CSCs. Our results also showed that MST-312 treatment inhibited SDCs more strongly than PCs and may therefore be useful as a complementary targeted therapy against renal CSCs in the future.
View details for DOI 10.3389/fonc.2019.01302
View details for PubMedID 31921617
View details for PubMedCentralID PMC6915099
High GD2 expression defines breast cancer cells with enhanced invasiveness.
Experimental and molecular pathology
2019; 109: 25-35
Breast cancer is the most frequently diagnosed cancer among women. Cancer stem cells (CSCs) are suggested to be responsible for tumor initiation, progression, metastasis, recurrence and drug resistance. This study was conducted to evaluate the clinical significance of GD2, a newly suggested CSC marker and two other traditional CSC markers, CD44 and CD24 in breast cancer patients.A total of 168 primary breast cancer tissues were evaluated in terms of GD2, CD44 and CD24 expression using tissue microarray. Then, the correlation of expression levels of these markers with patients' clinicopathological characteristics was assessed.Higher GD2 expression was mainly found in patients with advanced histological grade (p = 0.02), presence of lymph node invasion (p = 0.04), larger size of tumors (p = 0.04) and older age (p = 0.04). Breast cancer samples with advanced histological grade also showed higher CD44 (p = 0.03) and CD24 expression (p = 0.05). A significant positive association was found between increased CD24 expression and lymph node involvement (p = 0.01). Furthermore, GD2-high/CD44-high/CD24-low phenotype was frequently seen in breast cancer samples with positive lymph node involvement (p = 0.05).In summary, increased expression of GD2 may define more aggressive tumor behavior in breast cancer. GD2 can well be considered as a diagnostic and prognostic marker in breast cancer.
View details for DOI 10.1016/j.yexmp.2019.05.001
View details for PubMedID 31075227
Novel Agents in Heavily Pretreated Metastatic Gastric Cancer: More Shadows Than Lights.
Journal of oncology
2019; 2019: 5692317
Metastatic gastric cancer is still a disease with a poor prognosis. Recently, different novel agents (e.g., apatinib, nivolumab, TAS-102) have demonstrated a survival advantage compared with placebo for patients with heavily pretreated metastatic gastric cancer. Although the possible availability of active agents may be a desirable option in a very poor therapeutic scenario, clinical data from the recent studies with these drugs raise yet controversial issues. The purpose of this review is to briefly summarize the results of these novel drugs focusing on the limitations that bring some shadows on their positive therapeutic results.
View details for DOI 10.1155/2019/5692317
View details for PubMedID 31354820
View details for PubMedCentralID PMC6637676
Anti-PD-1 versus anti-PD-L1 therapy in patients with pretreated advanced non-small-cell lung cancer: a meta-analysis.
Future oncology (London, England)
2019; 15 (20): 2423-2433
Aim: At present three immune checkpoint inhibitors (ICIs), two anti-PD-1 (nivolumab and pembrolizumab) and one anti-PD-L1 (atezolizumab) can be used in pretreated non-small-cell lung cancer patients. The aim of this meta-analysis is an indirect comparison between anti-PD-1 and anti-PD-L1 inhibitors. Methods: Seven studies (>4000 patients) were considered. Results: Considering the overall survival ICIs showed very robust efficacy over docetaxel, while in terms of progression-free survival the therapy with ICIs is slightly favored. Anti-PD-1 gives a more significant benefit than anti-PD-L1; however, excluding the KEYNOTE 010 trial that enrolled only PD-L1-positive patients, the subgroup difference remains only in terms of progression-free survival. Conclusion: This meta-analysis confirms the superiority of ICIs over docetaxel in pretreated non-small-cell lung cancer patients and would indicate a slight benefit from anti-PD-1 than from anti-PD-L1 inhibitors, always keeping in mind the possible biases of this indirect comparison.
View details for DOI 10.2217/fon-2018-0868
View details for PubMedID 31237152
Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis.
2019; 19 (1): 558
Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC.Articles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta.Sixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22% (95% confidence interval [CI], 17-28) for all grades and 4% (95% CI, 2-6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and high-grade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10 weeks (interquartile range, 6-19.5 weeks) and varied depending on the organ system involved.The specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment.
View details for DOI 10.1186/s12885-019-5701-6
View details for PubMedID 31182061
View details for PubMedCentralID PMC6558759
Co-expression of TLR-9 and MMP-13 is associated with the degree of tumour differentiation in prostate cancer.
International journal of experimental pathology
2019; 100 (2): 123-132
In vitro experiments demonstrated that stimulation of Toll-like receptor 9 (TLR-9) by synthetic TLR-9 ligands induces the invasion of TLR-9-expressing prostate cancer cells through matrix metalloproteinase 13 (MMP-13). However, the clinical value of TLR-9 and MMP-13 co-expression in the pathophysiology of the prostate is unknown. In the study, we evaluated the expression levels and clinical significance of the TLR-9 and MMP-13 in a series of prostate tissues. One hundred and eighty prostate tissues including prostate cancer (PCa) (n = 137), high-grade prostatic intraepithelial neoplasia (HPIN) (n = 18) and benign prostatic hyperplasia (BPH) (n = 25) were immunostained for the TLR-9 and MMP-13 markers. Subsequently, the correlation between the TLR-9 and MMP-13 staining scores and clinicopathological parameters was obtained. Higher expressions of TLR-9 and MMP-13 were found in PCa and high-grade prostatic intraepithelial neoplasia compared to benign prostatic hyperplasia tissues. Among PCa samples, a positive relationship was revealed between the MMP-13 expression and Gleason score (P < 0.001). There was a significant correlation between TLR-9 expression and regional lymph node involvement (P = 0.04). The expression patterns of TLR-9 and MMP-13 markers demonstrated a reciprocal significant correlation between the two markers in the same series of prostate samples (P < 0.001). Furthermore, the Gleason score of TLR-9high /MMP-13high and TLR-9low /MMP-13low phenotypes showed a significant difference (P = 0.002). Higher expressions of TLR-9 and MMP-13 can confer aggressive behaviour to PCa. Therefore, these markers may be used as a valuable target for tailored therapy of PCa.
View details for DOI 10.1111/iep.12314
View details for PubMedID 31090157
View details for PubMedCentralID PMC6540662
Influence of Age and the Gleason Score in the Choice of Novel Hormonal Therapies Before and After Chemotherapy.
Cancer biotherapy & radiopharmaceuticals
2019; 34 (3): 141-146
Novel hormonal therapies (NHTs) have enriched the therapeutic armamentarium available for patients with castration-resistant prostate cancer. However, there is a need for clinical indicators able to drive treatment decisions and timing. The aim of this report is to perform a pooled analysis based on all available literature focused on prediction of efficacy and survival in patients treated with NHTs before and postchemotherapy.After reviewing the studies included in this work, the efficacy and the survival of NHTs according to age and Gleason score (GS) was focused.A total of eight studies were included in the analysis. With regard to age, the survival hazard ratio shows a better outcome, for both elderly and young patients, in postchemotherapy studies. With regard to progression-free survival, the subgroup analysis of pre- and postchemotherapy studies demonstrates the effect of NHTs on the reduction of risk of progression is greater in prechemotherapy studies irrespective of age. With regard to GS, NHTs show higher efficacy when administered postchemotherapy in patients with GS <8, whereas in patients with GS ≥8 NHTs are more effective in the prechemotherapy setting.Given the limitations of a meta-analysis of data from the literature, the results show that progression-free survival is always higher when NHTs are administered prechemotherapy in comparison with postchemotherapy. This benefit, however, translates in a reduction of risk of death only in patients with GS ≥8. In the other patients, the risk of death decreases when NHTs are administered postchemotherapy.
View details for DOI 10.1089/cbr.2018.2702
View details for PubMedID 30620216
CD44 epithelial isoform inversely associates with invasive characteristics of colorectal cancer.
Biomarkers in medicine
2019; 13 (6): 419-426
Aim: There is no consensus regarding the clinical significance of CD44 and CD24 as cancer stem cell (CSC) marker in colorectal cancer (CRC). Methodology: A total of 494 CRC samples (2008-2017) were assessed for CD44 (epithelial isoform) and CD24 expression using tissue microarray. Results: CD24 individually or in combination with CD44 was not associated with any of the clinicopathologic characteristics of the tumor. CD44 expression was inversely associated with pathological Tumor, Node, Metastasis (pTNM) lower stages (p = 0.038) and lymphatic invasion (p = 0.05). Conclusion: In summary, the epithelial isoform of CD44 is inversely associated with invasive characteristics of CRC.
View details for DOI 10.2217/bmm-2018-0337
View details for PubMedID 30942083
Development and Validation of a Prognostic Signature for Malignant Pleural Mesothelioma.
Frontiers in oncology
2019; 9: 78
Introduction: Dysregulated genes play a critical role in the development and progression of cancer, suggesting their potential as novel independent biomarkers for cancer diagnosis and prognosis. Prognostic model-based gene expression profiles are not widely utilized in clinical medicine. We investigated the prognostic significance of an expression profile-based gene signature for outcome prediction in patients with malignant pleural mesothelioma (MPM). Methods: The gene expression profiles of a large cohort of patients with MPM were obtained and analyzed by repurposing publicly available microarray data. A gene-based risk score model was developed with the training dataset and then validated with the TCGA-MESO (mesothelioma) dataset. The time-dependent receiver operating characteristic (ROC) curve was used to evaluate the prognostic performance of survival prediction. The biological function of the prognostic genes was predicted using bioinformatics analysis. Results: Three genes in the training dataset (GSE2549) were identified as significantly associated with the overall survival (OS) of patients with MPM and were combined to develop a three-gene prognostic signature to stratify patients into low-risk and high-risk groups. The MPM patients of the training dataset in the low-risk group exhibited longer OS than those in the high-risk group (HR = 0.25, 95% CI = 0.11-0.56, P < 0.001). Similar prognostic values for the three-gene signature were observed in the validated TCGA-MESO cohort (HR = 0.53 95% CI = 0.33-0.85, P = 0.008). ROC analysis also demonstrated the good performance in predicting 3-year OS in the GEO and TCGA cohorts (KM-AUC for GEO = 0.989, KM-AUC for TCGA = 0.618). The C-statistic for the 3-gene model was 0.761. Validation with TCGA-MESO confirmed the model's ability to discriminate between risk groups in an alternative data set with fair performance (C-statistic: 0.68). Functional enrichment analysis suggested that these three genes may be involved in genetic and epigenetic events with known links to MPM. Conclusions: This study has identified and validated a novel 3-gene model to reliably discriminate patients at high and low risk of death in unselected populations of patients with MPM. Further larger, prospective multi-institutional cohort studies are necessary to validate this model.
View details for DOI 10.3389/fonc.2019.00078
View details for PubMedID 30828567
View details for PubMedCentralID PMC6384238
Induction of miR-31 causes increased sensitivity to 5-FU and decreased migration and cell invasion in gastric adenocarcinoma.
Bratislavske lekarske listy
2019; 120 (1): 35-39
Drug resistance is the main obstacle in the treatment of gastric cancer, the third most common cause of cancer-related death in the world. Due to their small size, easy entrance to cells and multiple targets, microRNAs (miRs) are considered novel and attractive targets. In the current study, parental MKN-45, MKN-45-control vector, and MKN-45-miR-31 populations were compared in terms of cell cycle transitions, migration, cell invasion, and proliferation. In addition, downstream targets of miR-31, including E2F6, and SMUG1 were examined using Real-time RT-PCR and western blotting. MKN-45-miR-31 showed an increased sensitivity to 5-FU, decreased migration and cell invasion compared to the control groups (p = 0.0001, p = 0.01 and p = 0.01, respectively). There was a significant increase in the percentage of cells in G1/pre-G1 phase in MKN-45-miR-31 relative to the control groups (p = 0.001). Induction of miR-31 expression in MKN-45 caused a significant reduction of E2F6 and SMUG1 genes. Our findings indicated that induction of miR-31 expression could increase drug sensitivity, and diminish tumor cell migration and invasion of gastric cancer cells. Therefore, miR-31 can be considered as a potential target molecule in the targeted therapy of gastric cancer (Fig. 2, Ref. 43). Keywords: gastric cancer, miR-31, drug resistance, E2F6, SMUG1.
View details for DOI 10.4149/BLL_2019_005
View details for PubMedID 30685990
Association of homeobox B13 (HOXB13) gene variants with prostate cancer risk in an Iranian population.
Medical journal of the Islamic Republic of Iran
2018; 32: 97
Background: Prostate cancer is a complex condition in which both genetic and environmental factors concomitantly contribute to the tumor initiation and progression. Recently, HOXB13 has been proposed as a susceptibility gene for prostate cancer. Objective: The present study was conducted to determine the existence of potential variations in HOXB13 gene in Iranian men with prostate cancer (PCa) compared to benign prostatic hyperplasia (BPH) cases. Methods: HOXB13 genetic status was screened in 51 samples, including 21 blood and tissue of PCa cases, and compared to 30 cases affected by BPH using PCR/sequencing. Then, the existence of potential association was investigated between genomic DNA alterations in blood and tissue PCa specimens. Results: Analysis of BPH tissues showed single nucleotide variations c.366C > T (rs) or c.513T > C (rs9900627) in exon 1, but not in exon 2. Evaluation of PCa tissues revealed 2 cases with both synonymous c.366C > T and c.513T > C variants and 2 cases with the synonymous c.366C > T variant in exon 1. The variants c.366C > T and c.513T > C, simultaneously or separately, were found in blood samples of PCa patients. The novel variant c.127A > G in exon 2 was detected in 1 PCa blood sample. Our analysis indicated a significant reciprocal correlation between HOXB13 mutation in the tissue and blood samples of PCa cases (p= 0.02). Conclusion: The variants in exon 2 of HOXB13 may influence the risk of prostate cancer. Also, evaluation of HOXB13 mutation may be considered as a novel marker for screening PCa. Further investigations are warranted to evaluate the clinical significance of HOXB13 in Iranian population.
View details for DOI 10.14196/mjiri.32.97
View details for PubMedID 31024864
View details for PubMedCentralID PMC6477883
Do statins improve outcomes for patients with non-small cell lung cancer? A systematic review and meta-analysis protocol.
2018; 8 (9): e022161
Lung cancer is the most common neoplasm and the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC), accounting for 85% of all lung cancer cases, is frequently diagnosed at an advanced and metastatic stage. In addition, survival of patients with NSCLC has not improved significantly over the recent decades. Statins are used as a cholesterol-lowering agent, but recently preclinical and clinical studies have revealed their anticancer effects. Thus, this systematic review and meta-analysis aims to clarify whether statins improve the prognosis of patients with NSCLC.We will search MEDLINE (PubMed), EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov with no restriction on language. Both randomised controlled trials (RCTs) and observational cohort studies evaluating the prognostic role of statins in patients with NSCLC will be included. The primary outcome will be overall survival, and the secondary outcomes will include cancer-specific survival, disease-free survival and cancer recurrence. Two assessors will assess the RCTs using the Cochrane Collaboration's risk of bias tool and the observational cohort studies according to ROBINS-I. Publication bias will be assessed by funnel plot using the STATA software v.13.1.No ethical issues are predicted. This systematic review and meta-analysis aims to describe the prognostic effects of statins in patients with NSCLC, which would help clinicians to optimise treatment for patients with NSCLC. These findings will be published in a peer-reviewed journal and presented at national and international conferences.CRD42016047524.
View details for DOI 10.1136/bmjopen-2018-022161
View details for PubMedID 30206083
View details for PubMedCentralID PMC6144318
Distribution of KRAS, DDR2, and TP53 gene mutations in lung cancer: An analysis of Iranian patients.
2018; 13 (7): e0200633
Lung cancer is the deadliest known cancer in the world, with the highest number of mutations in proto-oncogenes and tumor suppressor genes. Therefore, this study was conducted to determine the status of hotspot regions in DDR2 and KRAS genes for the first time, as well as in TP53 gene, in lung cancer patients within the Iranian population.The mutations in exon 2 of KRAS, exon 18 of DDR2, and exons 5-6 of TP53 genes were screened in lung cancer samples, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) using PCR and sequencing techniques.Analysis of the KRAS gene showed only a G12C variation in one large cell carcinoma (LCC) patient, whereas variants were not found in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) cases. The Q808H variation in the DDR2 gene was detected in one SCC sample, while no variant was seen in the ADC and LCC subtypes. Variations in the TP53 gene were seen in all NSCLC subtypes, including six ADC (13.63%), seven SCC (15.9%) and two LCC (4.54%). Forty-eight variants were found in the TP53 gene. Of these, 15 variants were found in coding regions V147A, V157F, Q167Q, D186G, H193R, T211T, F212L and P222P, 33 variants in intronic regions rs1625895 (HGVS: c.672+62A>G), rs766856111 (HGVS: c.672+6G>A) and two new variants (c.560-12A>G and c.672+86T>C).In conclusion, KRAS, DDR2, and TP53 variants were detected in 2%, 2.17% and 79.54% of all cases, respectively. The frequency of DDR2 mutation is nearly close to other studies, while KRAS and TP53 mutation frequencies are lower and higher than other populations, respectively. Three new putative pathogenic variants, for the first time, have been detected in Iranian patients with lung cancer, including Q808H in DDR2, F212L, and D186G in coding regions of TP53. In addition, we observed five novel benign variants, including Q167Q, P222P and T211T in coding sequence, and c.560-12A>G and c.672+86T>C, in intronic region of TP53. Mutations of KRAS and DDR2 were found in LCC and SCC subtypes, respectively, whereas mutations of TP53 were seen in SCC and ADC subtypes with higher frequencies and LCC subtype with lower frequency. Therefore, Iranian lung cancer patients can benefit from mutational analysis before starting the conventional treatment. A better understanding of the biology of these genes and their mutations will be critical for developing future targeted therapies.
View details for DOI 10.1371/journal.pone.0200633
View details for PubMedID 30048458
View details for PubMedCentralID PMC6061986
Molecular epidemiology of lung cancer in Iran: implications for drug development and cancer prevention.
Journal of human genetics
2018; 63 (7): 783-794
Epidemiological studies undertaken over the past decades reveal a gradual but progressive increase in the incidence and mortality attributable to lung cancer in the Islamic Republic of Iran, a sovereign state geographically situated at the crossroads of Central Eurasia and Western Asia. We identified references published in English and Persian through searches of PubMed, EMBASE, Web of Science, Scopus, and the Scientific Information Database (SID)-a specialized Iranian database, which indexes Iranian scientific journals-between inception and 15 September 2017. Of 1475 references identified through electronic searches, we reviewed the full text of 88 studies, and included 38 studies in the review. Potentially druggable NSCLC targets, which have been studied in Iran include EGFR, ALK, ERBB2, and KIT; but no studies were found, which examined the impact of MET, ROS1, BRAF, PIK3CA, and FGFR1 aberrations. We were able to identify some literature on DNA repair genes and xenobiotic metabolism, including TP53, TP63, ERCC2, XRCC2, SIRT1, PTEN, CYP1A1, CYP1B1, GSTT1, and GSTM1. We also found an increasing amount of research performed in relation to the tumor microenvironment and immune contexture, including CTLA4, MAGE, FOXP3, IFN-γ, and various interleukins, chemokines, and transcription factors; but did not identify any publication concerning the expression of PD-1/PD-L1 in lung cancer. Our survey of research performed in Iran has revealed a dearth of studies in topics, which are otherwise highly pursued in developed countries, but nevertheless, has begun to hint at a distinct biology of lung cancer in this part of the world.
View details for DOI 10.1038/s10038-018-0450-y
View details for PubMedID 29666465
- Resisting resistance to cancer immunotherapy. Thoracic cancer 2018; 9 (5): 507-508
Are EGFR tyrosine kinase inhibitors effective in elderly patients with EGFR-mutated non-small cell lung cancer?
Clinical and experimental medicine
2018; 18 (1): 15-20
EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib changed dramatically the history of metastatic non-small cell lung cancer (NSCLC) harbouring EGFR mutations. However, not enough data are available on the efficacy of these targeted drugs in elderly patients. The aim of this study is to analyse the available clinical data evaluating the efficacy of anti-EGFR therapies in elderly patients with advanced NSCLC carrying EGFR mutations. A literature-based meta-analysis of the results of randomized clinical trials was undertaken. Relevant publications from PubMed, the Cochrane Library, and abstracts from American Society of Clinical Oncology meetings were searched. Progression-free survival (PFS), as a measure of the efficacy of treatment, was the primary outcome investigated. The pooled analysis revealed an overall significant improvement in PFS (HR = 0.44, 95% CI 0.28-0.69; p = 0.0004) with the use of EGFR TKIs in EGFR-mutated NSCLC. The data stratification per age subgroups showed that EGFR TKIs were more effective in prolonging PFS in elderly patients, with HR 0.39 (p = 0.008), in comparison with young patients (HR = 0.48; p = 0.04). The results of this study suggest that EGFR TKIs have a significant effect in slowing down diseases progression in elderly patients with advanced NSCLC, therefore representing a valid therapeutic option in this age group.
View details for DOI 10.1007/s10238-017-0460-7
View details for PubMedID 28391544
Immunotherapy (excluding checkpoint inhibitors) for stage I to III non-small cell lung cancer treated with surgery or radiotherapy with curative intent.
The Cochrane database of systematic reviews
2017; 12: CD011300
Non-small cell lung cancer (NSCLC) is the most common lung cancer, accounting for approximately 80% to 85% of all cases. For patients with localised NSCLC (stages I to III), it has been speculated that immunotherapy may be helpful for reducing postoperative recurrence rates, or improving the clinical outcomes of current treatment for unresectable tumours. While several new agents have now entered phase III clinical trials, we felt a systematic review was needed to address the question of the effectiveness and safety of immunotherapy in patients with stages I to III NSCLC.To evaluate the effectiveness and safety of immunotherapy (excluding checkpoint inhibitors) in patients with localised NSCLC (stages I to III) who received surgery or radiotherapy with curative intent.We searched the following databases (from inception to 20 January 2017): CENTRAL, MEDLINE, Embase, and CINAHL, and five trial registers. We also manually checked abstracts or reports from relevant conference proceedings and the reference lists of included trials.We searched for randomised controlled trials (RCTs) in adults (≥ 18 years) with histologically-confirmed early-stage (stages I to III) NSCLC after surgical resection, and those with unresectable locally advanced stage III NSCLC who had received radiotherapy with curative intent. For patients who had received primary surgical treatment, postoperative radiotherapy or chemoradiotherapy was allowed if it was used for both experimental and control groups.Two review authors independently selected eligible trials, assessed risk of bias, and extracted data. We used survival analysis to pool time-to-event data, expressing the intervention effect as a hazard ratio (HR). We calculated risk ratios (RR) for dichotomous data, and mean differences for continuous data, with 95% confidence intervals (CI). Due to clinical heterogeneity (immunotherapeutic agents with different underlying mechanisms), we used random-effects models for our meta-analyses.We identified nine eligible trials that randomised 4940 participants, who had received surgical resection or curative radiotherapy, to either an immunotherapy group or a control group. Included immunological interventions were active immunotherapy (i.e. Bacillus Calmette-Guérin (BCG)), adoptive cell transfer (i.e. transfer factor (TF), tumour-infiltrating lymphocytes (TIL), dendritic cell-cytokine induced killer (DC-CIK), and antigen-specific cancer vaccines (melanoma-associated antigen 3 (MAGE-A3) and L-BLP25). Except for one small trial, which provided insufficient information for risk assessment, we assessed five studies at high risk of bias for at least one of the seven biases studied; we considered the risk of bias in the other three trials to be low. We included data from seven of the nine trials in the meta-analyses (4695 participants). We pooled data from 3693 participants from the three high quality RCTs to evaluate overall survival (OS) and progression-free survival (PFS). We found a small, but not statistically significant, improvement in OS (HR 0.94, 95% CI 0.83 to 1.06; P = 0.35), and PFS (HR 0.93, 95% CI 0.81 to 1.07; P = 0.19; high-quality evidence). The addition of immunotherapy resulted in a small, but not statistically significant, increased risk of having any adverse event (RR 1.15, 95% CI 0.97 to 1.37; P = 0.11, three trials, 3955 evaluated participants, moderate-quality evidence), or severe adverse events (RR 1.10, 95% CI 0.88 to 1.39; four trials, 4362 evaluated participants; low-quality evidence).We analysed data from six studies for one-, two-, and three-year survival rates (4265 participants), and from six studies for five-year survival rates (4234 participants). We observed no clear between-group differences (low-quality evidence for one- and two-year survival rates, and moderate-quality evidence for three- and five-year survival rate).No trial reported the overall response rates; only one trial provided health-related quality of life results.The current literature does not provide evidence that suggests a survival benefit from adding immunotherapy (excluding checkpoint inhibitors) to conventional curative surgery or radiotherapy, for patients with localised NSCLC (stages I to III). The addition of vaccine-based immunotherapy might increase the risk of adverse events. Several ongoing trials with immune checkpoints inhibitors (PD-1/PD-L1) might bring new insights for role of immunotherapy for patients with stages I to III NSCLC.
View details for DOI 10.1002/14651858.CD011300.pub2
View details for PubMedID 29247502
View details for PubMedCentralID PMC6486009
Lgr5High/DCLK1High phenotype is more common in early stage and intestinal subtypes of gastric carcinomas.
Cancer biomarkers : section A of Disease markers
2017; 20 (4): 563-573
Gastric carcinoma is the third most common malignancy and is one of the main causes of cancer deaths worldwide. Cancer stem cells (CSCs) are a subpopulation of tumour cells capable of self-renewal and differentiation, likely responsible for the initiation, recurrence, metastasis and chemo/radio-resistance.This study was conducted to evaluate the expression patterns and clinicopathologic significance of putative CSC markers, Lgr5 and DCLK1, in gastric carcinoma.The expression levels of Lgr5 and DCLK1 were examined in a well-defined series of gastric carcinoma tissues, including 75 (80%) from intestinal and 19 (20%) from diffuse subtypes, using tissue microarray (TMA). In addition, the correlation of the expression of these markers with clinicopathological factors was explored.Higher expressions of Lgr5 and DCLK1 were mainly detected in intestinal subtypes of gastric carcinomas compared to diffuse subtypes (P= 0.005 and P= 0.050, respectively). We also found a higher expression of Lgr5 and DCLK1 more frequently in well-differentiated gastric carcinoma cases (P< 0.001 and P= 0.007). The combined analysis demonstrated that the co-expression of Lgr5 and DCLK1 (Lgr5High/DCLK1High) was more common in intestinal subtypes (P= 0.025) and well-differentiated gastric carcinoma samples (P< 0.001). Interestingly, there was a significant correlation between Lgr5High/DCLK1High phenotype and early-stage gastric carcinoma specimens (P= 0.045).Our findings indicated that the Lgr5High/DCLK1High expression pattern may be considered as a signature phenotype for intestinal subtypes of gastric carcinoma.
View details for DOI 10.3233/CBM-170383
View details for PubMedID 28946555
MicroRNA-31 inhibits RhoA-mediated tumor invasion and chemotherapy resistance in MKN-45 gastric adenocarcinoma cells.
Experimental biology and medicine (Maywood, N.J.)
2017; 242 (18): 1842-1847
microRNAs are small single-stranded non-coding RNA molecules which modify gene expression by silencing potential target genes. The aberrant expression of RhoA, a small GTPase protein of Rho family, is involved in gastric cancer tumorigenesis. Since miR-31 is a pleomorphic molecule, we evaluated the miR-31/RhoA axis in inducing the malignant phenotype of gastric cancer cells MKN-45. Also, the clinicopathological significance of RhoA was investigated in a well-defined collection of gastric carcinomas which were embedded in tissue microarray blocks. Induction of miR-31 in MKN-45 followed by suppression of RhoA expression resulted in increased sensitivity to 5-fluorouracil, inhibition of cell proliferation, and invasion compared to the control groups. Immunohistochemical analysis in gastric adenocarcinoma patients' samples showed significantly higher expression of RhoA in diffuse versus intestinal subtype tumors ( P = 0.009), poorly differentiated versus well and moderately differentiated tumors ( P = 0.03) and the presence of vascular invasion versus the absence of vascular invasion ( P = 0.04). Our findings suggest a critical role for miR-31, as a tumor suppressor gene, in gastric cancer tumorigenesis by targeting the RhoA. Impact statement Gastric cancer ranks as the third leading cause of cancer-associated deaths worldwide. The RhoA gene encodes a small GTPase protein of Rho family (RhoA) that its dysregulation is associated with cell motility and invasion. A strong line of evidence supports the regulation of RhoA by a number of miRs, including miR-31 in tumors. Our findings revealed that miR-31 is involved in gastric cancer tumorigenesis as a tumor suppressor gene. Through down-regulation of RhoA, miR-31 decreased cell proliferation, migration, and invasion in gastric cancer cells. In addition, induction of miR-31 increased sensitivity to 5-FU; thus, increasing its tissue concentrations could be a potential target for treatment of gastric cancer in the future.
View details for DOI 10.1177/1535370217728460
View details for PubMedID 28836853
View details for PubMedCentralID PMC5714140
DNA Microarray for Rapid Detection and Identification of Food and Water Borne Bacteria: From Dry to Wet Lab.
The open microbiology journal
2017; 11: 330-338
A rapid, accurate, flexible and reliable diagnostic method may significantly decrease the costs of diagnosis and treatment. Designing an appropriate microarray chip reduces noises and probable biases in the final result.The aim of this study was to design and construct a DNA Microarray Chip for a rapid detection and identification of 10 important bacterial agents.In the present survey, 10 unique genomic regions relating to 10 pathogenic bacterial agents including Escherichia coli (E.coli), Shigella boydii, Sh.dysenteriae, Sh.flexneri, Sh.sonnei, Salmonella typhi, S.typhimurium, Brucella sp., Legionella pneumophila, and Vibrio cholera were selected for designing specific long oligo microarray probes. For this reason, the in-silico operations including utilization of the NCBI RefSeq database, Servers of PanSeq and Gview, AlleleID 7.7 and Oligo Analyzer 3.1 was done. On the other hand, the in-vitro part of the study comprised stages of robotic microarray chip probe spotting, bacterial DNAs extraction and DNA labeling, hybridization and microarray chip scanning. In wet lab section, different tools and apparatus such as Nexterion® Slide E, Qarraymini spotter, NimbleGen kit, TrayMixTM S4, and Innoscan 710 were used.A DNA microarray chip including 10 long oligo microarray probes was designed and constructed for detection and identification of 10 pathogenic bacteria.The DNA microarray chip was capable to identify all 10 bacterial agents tested simultaneously. The presence of a professional bioinformatician as a probe designer is needed to design appropriate multifunctional microarray probes to increase the accuracy of the outcomes.
View details for DOI 10.2174/1874285801711010330
View details for PubMedID 29290845
View details for PubMedCentralID PMC5737027
Immune-related adverse events associated with PD-1 and PD-L1 inhibitors for nonsmall cell lung cancer: Protocol for a systematic review and meta-analysis.
2017; 96 (44): e8407
Nonsmall cell lung cancer accounts for approximately 80% of all lung cancers, and approximately 75% of cases are diagnosed in the middle and late stages of disease. Unfortunately, limited treatment does not improve the prognosis of advanced disease. Monoclonal antibodies targeting programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) represent a new treatment paradigm for nonsmall cell lung cancer. Nevertheless, the immune-related adverse events (irAEs) associated with PD-1 and PD-L1 inhibitors are unique, and early recognition and treatment of these events are essential.A systematic literature search will be performed using the EMBASE, MEDLINE, and Cochrane databases to identify relevant articles published in any language. Randomized clinical trials, case series, and case reports of PD-1 and PD-L1 inhibitors in the treatment of nonsmall cell lung cancer will be included. All meta-analyses will be performed using RevMan software. The quality of the studies will be evaluated using the guidelines listed in the Cochrane Handbook. If the necessary data are available, then subgroup analyses will be performed for high-, median-, and low-dose cohorts. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements will be followed until the findings of the systematic review and meta-analysis are reported.This will be the first systematic review and meta-analysis to describe previously reported irAEs related to PD-1 and PD-L1 inhibitors in the treatment of nonsmall cell lung cancer.
View details for DOI 10.1097/MD.0000000000008407
View details for PubMedID 29095271
View details for PubMedCentralID PMC5682790
Differential role of Wnt signaling and base excision repair pathways in gastric adenocarcinoma aggressiveness.
Clinical and experimental medicine
2017; 17 (4): 505-517
Aberrant activation of Wnt and base excision repair (BER) signaling pathways are implicated in tumor progression and chemotherapy resistance in gastric adenocarcinoma. This study was conducted to clarify the role of E2F6 and RhoA, components of the Wnt signaling pathway, and SMUG1, a component of the BER pathway in gastric adenocarcinoma. Expression levels and clinicopathological significance of three biomarkers, namely E2F6, RhoA, and SMUG1, as potential signaling molecules involved in tumorigenesis and aggressive behavior, were examined using tissue microarray. Our analysis showed a relative increase in the expression of E2F6 in gastric adenocarcinoma with no lymph node metastasis (χ 2, P = 0.04 and OR, P = 0.08), while overexpression of RhoA and SMUG1 was found more often in the diffuse subtype of gastric adenocarcinoma as compared to the intestinal subtype (χ 2, P = 0.05, OR, P = 0.08 and χ 2, P = 0.001, OR, P = 0.009, respectively). Higher expression of RhoA was frequently seen in tumors with vascular invasion (χ 2, P = 0.01 and OR, P = 0.01). In addition, increased expression of SMUG1 was found more often in poorly differentiated tumors (χ 2, P = 0.01 and OR, P = 0.01). The distinct phenotype of E2F6Low/SMUG1High was more common in poorly differentiated tumors (P = 0.04) and with omental involvement (P = 0.01). The RhoAHigh/SMUG1High expression pattern was significantly more often found in diffuse subtype compared to the intestinal subtype (P = 0.001) as well as in poorly differentiated tumors (P = 0.004). The E2F6Low/SMUG1High and RhoAHigh/SMUG1High phenotypes can be considered as aggressive phenotypes of gastric adenocarcinoma. Our findings also demonstrated the synergistic effect of RhoA and SMUG1 in conferring tumor aggressiveness in diffuse subtype of gastric adenocarcinoma.
View details for DOI 10.1007/s10238-016-0443-0
View details for PubMedID 27909884
Antimicrobial Peptides As Biologic and Immunotherapeutic Agents against Cancer: A Comprehensive Overview.
Frontiers in immunology
2017; 8: 1320
Antimicrobial peptides (AMPs) are a pervasive and evolutionarily ancient component of innate host defense which is present in virtually all classes of life. In recent years, evidence has accumulated that parallel or de novo mechanisms by which AMPs curb infectious pathologies are also effective at restraining cancer cell proliferation and dissemination, and have consequently stimulated significant interest in their deployment as novel biologic and immunotherapeutic agents against human malignancies. In this review, we explicate the biochemical underpinnings of their tumor-selectivity, and discuss results of recent clinical trials (outside of oncologic indications) which substantiate their safety and tolerability profiles. Next, we present evidence for their preclinical antitumor activity, systematically organized by the major and minor classes of natural AMPs. Finally, we discuss the barriers to their clinical implementation and envision directions for further development.
View details for DOI 10.3389/fimmu.2017.01320
View details for PubMedID 29081781
View details for PubMedCentralID PMC5645638
Increased Expression of ALDH1A1 in Prostate Cancer is Correlated With Tumor Aggressiveness: A Tissue Microarray Study of Iranian Patients.
Applied immunohistochemistry & molecular morphology : AIMM
2017; 25 (8): 592-598
Subpopulations of prostate cancer (PCa) cells expressing putative stem cell markers possess the ability to promote tumor growth, maintenance, and progression. This study aimed to evaluate the expression patterns and clinical significance of putative stem cell marker aldehyde dehydrogenase 1 A1 (ALDH1A1) in prostate tumor tissues.ALDH1A1 expression was examined in a well-defined series of prostate tissues, including 105 (68%) samples of PCa, 21 (13%) samples of high-grade prostatic intraepithelial neoplasia, and 31 (19%) samples of benign prostate hyperplasia, which were embedded in tissue microarray blocks. The correlation of ALDH1A1 expression with clinicopathologic parameters was also assessed.There was a significant difference between the expression level of ALDH1A1 in PCa compared with the high-grade prostatic intraepithelial neoplasia and benign prostate hyperplasia samples (P<0.001). PCa cells expressing ALDH1A1 were more often seen in samples with advanced Gleason score (P=0.05) and high serum prostate specific antigen level (P=0.02). In addition, a positive correlation was found between ALDH1A1 expression and primary tumor stage and regional lymph node involvement (P=0.04 and 0.03, respectively).The significant association between ALDH1A1 expressions with Gleason score indicates the potential role of this protein in PCa tumorigenesis and aggressive behavior; therefore, this cancer stem cell marker can be used as a promising candidate for targeted therapy of PCa, especially those with high Gleason score.
View details for DOI 10.1097/PAI.0000000000000343
View details for PubMedID 26894647
Cancer stem cell research in Iran: potentials and challenges.
Future oncology (London, England)
2017; 13 (20): 1809-1826
Treatment modalities can reduce cancer-related mortality; however, a majority of patients develop drug resistance, metastasis and relapse. It has been proposed that tumorigenic characteristics of tumors are related to a proportion of cancer cells, termed cancer stem cells (CSCs). Following the first evidence regarding the existence of CSC population in acute myeloid leukemia in 1997, publications in CSCs field showed an explosive trend in all cancer types around the world. First research paper in the field of CSCs in Iran was published in 2004 on prostate cancer. Subsequently, an annual number of publications in the field of CSCs displayed a rapidly growing trend. Therefore, in the current review, we have presented a comprehensive evaluation of the CSCs research in Iran.
View details for DOI 10.2217/fon-2017-0091
View details for PubMedID 28776391
Lung cancer and β-glucans: review of potential therapeutic applications.
Investigational new drugs
2017; 35 (4): 509-517
The potential of natural substances with immunotherapeutic properties has long been studied. β-glucans, a cell wall component of certain bacteria and fungi, potentiate the immune system against microbes and toxic substances. Moreover, β-glucans are known to exhibit direct anticancer effects and can suppress cancer proliferation through immunomodulatory pathways. Mortality of lung cancer has been alarmingly increasingly worldwide; therefore, treatment of lung cancer is an urgent necessity. Numerous researchers are now dedicated to using β-glucans as a therapy for lung cancer. In the present attempt, we have reviewed the studies addressing therapeutic effects of β-glucans in primary and metastatic lung cancer published in the time period of 1991-2016.
View details for DOI 10.1007/s10637-017-0449-9
View details for PubMedID 28303529
Clinical significance of endothelial cell marker CD34 and mast cell marker CD117 in prostate adenocarcinoma.
Pathology, research and practice
2017; 213 (6): 612-618
Prostate cancer is the second cause of cancer-related deaths in men and this is attributed to its aggressiveness and metastatic identity. Our objective was to evaluate the expression patterns of endothelial cell marker CD34 and mast cell marker CD117 in prostate adenocarcinoma (PCa) compared to benign prostate tissue and their relation to the clinicopathological features. A total of 90 prostate samples, including 45 PCa and 45 benign prostate tissues were immunohistochemically examined for the detection of CD34 and CD117 markers. The expression of these markers was also correlated with clinicopathological parameters. Significant overexpression of CD34 was found in PCa group compared to benign prostate tissues (P≤0.001). The expression of CD34 and CD117 in PCa with advanced Gleason score was more than PCa with early Gleason score (P=0.02 and P=0.005, respectively). A significant positive correlation was observed between CD34 expression and the level of total serum prostate specific antigen (sPSA) (P=0.006). In addition, CD34High/CD117High phenotype was frequently observed in PCa cases compared to benign prostate tissues (P≤0.001). There was a positive significant association between CD34High/CD117High phenotype with advanced Gleason score (P≤0.001) and total sPSA level (P=0.02). Our findings showed that increased expression of CD34 and CD117 markers confer tumor progression and aggressiveness on PCa. These molecules may be good candidates for targeted therapy of PCa patients.
View details for DOI 10.1016/j.prp.2017.04.027
View details for PubMedID 28552539
Expression of Cancer Stem Cell Markers OCT4 and CD133 in Transitional Cell Carcinomas.
Applied immunohistochemistry & molecular morphology : AIMM
2017; 25 (3): 196-202
Treatment failure, recurrence, and metastasis in bladder cancer are attributed to a subset of tumor cells expressing cancer stem cell (CSC) markers. This study aimed to explore the expression levels and the clinical significance of putative CSC markers OCT4 and CD133 in bladder cancer.Tissue microarray-based immunohistochemical analysis was applied to investigate the expression patterns of potential CSC markers OCT4 and CD133 in bladder cancer samples. The correlation between the expressions of each marker and clinicopathologic parameters was then analyzed.There was a significant association between OCT4 expression and the TNM stage of bladder cancer (P<0.001). Our analysis demonstrated a significant association between the intensity of staining and the presence of lamina propria and muscularis propria invasion (P=0.02 and 0.02, respectively), whereas a relative inverse correlation was found between CD133 expression with lamina propria invasion (P=0.051) and muscularis propria invasion (P=0.07).The correlation of OCT4, but not CD133, with the invasiveness of bladder cancer revealed that OCT4 can be considered as a key regulator of tumor progression, aggressive behavior, and metastasis; therefore, OCT4 can be a potential marker for targeted therapy of bladder cancer.
View details for DOI 10.1097/PAI.0000000000000291
View details for PubMedID 26945449
Evidence for embryonic stem-like signature and epithelial-mesenchymal transition features in the spheroid cells derived from lung adenocarcinoma.
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine
2016; 37 (9): 11843-11859
Identification of the cellular and molecular aspects of lung cancer stem cells (LCSCs) that are suggested to be the main culprit of tumor initiation, maintenance, drug resistance, and relapse is a prerequisite for targeted therapy of lung cancer. In the current study, LCSCs subpopulation of A549 cells was enriched, and after characterization of the spheroid cells, complementary DNA (cDNA) microarray analysis was applied to identify differentially expressed genes (DEGs) between the spheroid and parental cells. Microarray results were validated using quantitative real-time reverse transcription-PCR (qRT-PCR), flow cytometry, and western blotting. Our results showed that spheroid cells had higher clonogenic potential, up-regulation of stemness gene Sox2, loss of CD44 expression, and gain of CD24 expression compared to parental cells. Among a total of 160 genes that were differentially expressed between the spheroid cells and the parental cells, 104 genes were up-regulated and 56 genes were down-regulated. Analysis of cDNA microarray revealed an embryonic stem cell-like signature and over-expression of epithelial-mesenchymal transition (EMT)-associated genes in the spheroid cells. cDNA microarray results were validated at the gene expression level using qRT-PCR, and further validation was performed at the protein level by flow cytometry and western blotting. The embryonic stem cell-like signature in the spheroid cells supports two important notions: maintenance of CSCs phenotype by dedifferentiating mechanisms activated through oncogenic pathways and the origination of CSCs from embryonic stem cells (ESCs). PI3/AKT3, as the most common up-regulated pathway, and other pathways related to aggressive tumor behavior and EMT process can confer to the spheroid cells' high potential for metastasis and distant seeding.
View details for DOI 10.1007/s13277-016-5041-y
View details for PubMedID 27048287
Evaluation of anaplastic lymphoma kinase expression in nonsmall cell lung cancer;a tissue microarray analysis.
Journal of cancer research and therapeutics
2016; 12 (2): 1065-9
The oncogenic form of anaplastic lymphoma kinase (ALK) gene is an attractive candidate marker for diagnostic and therapeutic purposes in several malignancies, including nonsmall cell lung cancer (NSCLC). This study aimed to examine the expression levels and clinical significance of ALK in a series of NSCLC tumors.We retrospectively reviewed 140 samples of NSCLC, including 64 (46%) squamous cell carcinoma (SCC), 62 (44%) adenocarcinoma (ADC), and 14 (10%) large cell carcinoma (LCC) for expression of ALK using immunohistochemistry; and immunostaining patterns were correlated with clinicopathological parameters.Expression of ALK was significantly different between SCC with ADC (P < 0.001) and LCC samples (P < 0.001). The highest level of ALK expression was found in ADC cases with poor differentiation and high nuclear grade (P = 0.005 and P = 0.005, respectively). Furthermore, high level of ALK expression was more often observed in ADC cases with poor prognosis features (P = 0.013).These findings suggested that ALK can be considered as a promising target in the targeted therapy in patients with lung ADC.
View details for DOI 10.4103/0973-1482.170940
View details for PubMedID 27461700
Comparative expression analysis of putative cancer stem cell markers CD44 and ALDH1A1 in various skin cancer subtypes.
The International journal of biological markers
2016; 31 (1): e53-61
Skin cancers, particularly melanoma, are initiated and maintained by a subpopulation of tumor cells expressing stemness markers that are called cancer stem cells (CSCs). This study aimed to evaluate the expression levels and clinicopathological significance of the putative CSC markers CD44 and ALDH1A1 in patients with skin cancer.The expression levels of CD44 and ALDH1A1 were investigated in 107 skin cancer specimens including 58 (54%) basal cell carcinomas (BCC), 37 (35%) squamous cell carcinomas (SCC), and 12 (11%) melanomas using the tissue microarray (TMA) technique. The correlation of the expression levels of these markers and clinicopathological parameters was then analyzed.The expression levels of CD44 and ALDH1A1 were significantly higher in melanoma patients than patients with SCC or BCC (p<0.001 and p = 0.002, respectively). A higher level of CD44 expression was more often found in melanoma tumor cells with a higher rate of recurrence (p = 0.029) and in SCC cases with ulceration (p = 0.01), while there was no significant correlation between ALDH1A1 expression and other clinicopathological parameters. Similarly, coexpression of CD44 and ALDH1A1 (CD44high/ALDH1A1high) was significantly observed in melanoma samples (p<0.001).These findings suggest that a CD44high/ALDH1A1high phenotype in melanoma and a CD44high phenotype in SCC can be considered candidates for targeted therapy of skin cancers aiming at CSCs.
View details for DOI 10.5301/jbm.5000165
View details for PubMedID 26391478
Diagnostic and prognostic accuracy of miR-21 in renal cell carcinoma: a systematic review protocol.
2016; 6 (1): e009667
Renal cell carcinoma (RCC) is the most common neoplasm in adult kidneys. One of the most important unmet medical needs in RCC is a prognostic biomarker to enable identification of patients at high risk of relapse after nephrectomy. New biomarkers can help improve diagnosis and hence the management of patients with renal cancer. Thus, this systematic review aims to clarify the prognostic and diagnostic accuracy of miR-21 in patients with RCC.We will include observational studies evaluating the diagnostic and prognostic roles of miR-21 in patients with renal cancer. The index test and reference standards should ideally be performed on all patients. We will search PubMed, SCOPUS and ISI Web of Science with no restriction of language. The outcome will be survival measures in adult patients with RCC. Study selection and data extraction will be performed by two independent reviewers. QUADAS-1 will be used to assess study quality. Publication bias and data synthesis will be assessed by funnel plots and Begg's and Egger's tests using Stata software V.11.1.No ethical issues are predicted. These findings will be published in a peer-reviewed journal and presented at national and international conferences.This systematic review protocol is registered in the PROSPERO International Prospective Register of Systematic Reviews, registration number CRD42015025001.
View details for DOI 10.1136/bmjopen-2015-009667
View details for PubMedID 26729387
View details for PubMedCentralID PMC4716203
Comparative gene-expression profiling of CD133(+) and CD133(-) D10 melanoma cells.
Future oncology (London, England)
2015; 11 (17): 2383-93
The present study aimed to compare the gene-expression profiling of CD133(+) and CD133(-) D10 cells.Cancer stem cell-like properties and gene-expression profiling of CD133(+) D10 cells versus CD133(-) cells were evaluated.The CD133(+) D10 cells showed significantly higher clonogenic and spheroid forming potential, also higher expression of stemness genes NANOG and OCT4A compared with the CD133(-) cells. Gene-expression profiling of CD133(+) versus CD133(-) D10 cells revealed that 130 genes including ABC transporter superfamily (ABCC1, ABCG2 and ABCC6) were upregulated, while 61 genes including apoptosis modifying genes (CASP8 and TNFRSF4) were downregulated.We conclude that many genes involved in drug resistance and tumor aggressiveness are upregulated in CD133(+) D10 cells and targeting them might be an efficient strategy for treatment of melanoma.
View details for DOI 10.2217/fon.15.174
View details for PubMedID 26285774
Differential Expression of Cancer Stem Cell Markers ALDH1 and CD133 in Various Lung Cancer Subtypes.
2015; 33 (7): 294-302
Cancer stem cells (CSCs) are hypothesized to be the main culprit of lung cancer progression. Clinicopathological significance of stem cell markers CD133 and ALDH1 in a large group of lung cancer patients was evaluated. ALDH1 and CD133 had higher expression levels in the NSCLC compared to the SCLC. Over-expression of both ALDH1 and CD133 markers was exclusively found in SCC and ADC. Low level of ALDH1 expression was strongly correlated with poor differentiation in ADC cases. Thus, ALDH1(high)/CD133(high) phenotype can be considered as a CSC marker in some lung cancer subtypes.
View details for DOI 10.3109/07357907.2015.1034869
View details for PubMedID 26046383
Clinical significance of putative cancer stem cell marker CD44 in different histological subtypes of lung cancer.
Cancer biomarkers : section A of Disease markers
2014; 14 (6): 457-67
According to the cancer stem cell theory, tumors originate from a subset of cells known as cancer stem cells (CSCs) that are responsible for tumor initiation, resistance and relapse. CD44 is a cell adhesion molecule that can aid in the identification of CSCs in various malignancies.The purpose of the current study is to evaluate the expression level and clinical significance of CD44 in lung cancer samples.One hundred and ninety-five lung tumor samples including 74 (38%) squamous cell carcinomas (SCC), 61 (31%) adenocarcinomas (ADC), 23 (12%) large cell carcinoma (LCC) in non-small cell lung cancer (NSCLC) group and 37 (19%) small cell lung cancer (SCLC) samples were examined for the expression of CD44 using immunohistochemistry method. The correlation of CD44 expression with clinicopathological parameters as well as Ki-67 status was also assessed.Univariate analysis demonstrated that CD44 expression was significantly higher in NSCLC compared to SCLC (P < 0.001). Among NSCLC, higher level of CD44 expression was found in SCC compared to ADC (P< 0.001) and LCC (P=0.046). Increased expression of CD44 was significantly correlated with higher grade tumors which correspond to poor prognosis in SCC (P=0.012) and the lower level of CD44 expression was more often found in well differentiated ADC tumors (P=0.03). In addition, high expression of CD44 was significantly associated with decreased level of proliferative marker Ki-67 (P=0.04).CD44 could be a valuable tool for the study of lung CSCs and provide a novel therapeutic target for treatment of the patients with lung cancer in combination with conventional therapy.
View details for DOI 10.3233/CBM-140424
View details for PubMedID 25335738
CD44 and CD24 cannot act as cancer stem cell markers in human lung adenocarcinoma cell line A549.
Cellular & molecular biology letters
2014; 19 (1): 23-36
Cancer stem cells (CSCs) are subpopulations of tumor cells that are responsible for tumor initiation, maintenance and metastasis. Recent studies suggested that lung cancer arises from CSCs. In this study, the expression of potential CSC markers in cell line A549 was evaluated. We applied flow cytometry to assess the expression of putative stem cell markers, including aldehyde dehydrogenase 1 (ALDH1), CD24, CD44, CD133 and ABCG2. Cells were then sorted according to the expression of CD44 and CD24 markers by fluorescence-activated cell sorting (FACS) Aria II and characterized using their clonogenic and sphere-forming capacity. A549 cells expressed the CSC markers CD44 and CD24 at 68.16% and 54.46%, respectively. The expression of the putative CSC marker ALDH1 was 4.20%, whereas the expression of ABCG2 and CD133 was 0.93%. Double-positive CD44/133 populations were rare. CD44(+)/24(+) and CD44(+)/CD24(-/low) subpopulations respectively exhibited 64% and 27.92% expression. The colony-forming potentials in the CD44(+)/CD24(+) and CD44(+)/CD24(-/low) subpopulations were 84.37 ± 2.86% and 90 ± 3.06%, respectively, while the parental A549 cells yielded 56.65 ± 2.33% using the colony-formation assay. Both isolated subpopulations formed spheres in serum-free medium supplemented with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). CD44 and CD24 cannot be considered potential markers for isolating lung CSCs in cell line A549, but further investigation using in vivo assays is required.
View details for DOI 10.2478/s11658-013-0112-1
View details for PubMedID 24363164
View details for PubMedCentralID PMC6275711