Comparative effects of Nucleostemin silencing in human Molt-4 and Jurkat leukemia T-ALL cells

     Nucleostemin (NS), a stem cell-abundant nucleolar protein, is critical for maintaining the self-renewal and proliferative properties of normal and cancerous stem cells. Recent data suggests that NS signaling is important for proliferation of T-cells and leukemia cells. This study was conducted to verify the role of NS in pathogenesis and treatment of T-cell acute lymphocytic leukemia (T-ALL). Our results revealed that RNA interference-mediated NS silencing primarily affected clonogenicproperty of T-ALL cells by limiting their self-renewal potential in vitro.These effects were accompanied with inhibition of proliferation and early apoptosis in Jurkat cells (p53-null) while late apoptosis in Molt-4 (p53 functional) T-ALL cells. Collectively, our results suggest that NS is a critical regulator in self-renewal and apoptosis of differentT-ALL cells. This suggests therapeutic potential of this gene in leukemia

Nucleostemin depletion induces post-G1 arrest apoptosis in chronic myelogenous leukemia K562 cells

Abstract Purpose: Despite significant improvements in treatment of chronic myelogenous leukemia (CML), the emergence of leukemic stem cell (LSC) concept questioned efficacy of current therapeutical protocols. Remaining issue on CML includes finding and targeting of the key genes responsible for self-renewal and proliferation of LSCs. Nucleostemin (NS) is a new protein localized in the nucleolus of most stem cells and tumor cells which regulates their self-renewal and cell cycle progression. The aim of this study was to investigate effects of NS knocking down in K562 cell line as an in vitro model of CML. Methods: NS gene silencing was performed using a specific small interfering RNA (NS-siRNA). The gene expression level of NS was evaluated by RT-PCR. The viability and growth rate of K562 cells were determined by trypan blue exclusion test. Cell cycle distribution of the cells was analyzed by flow cytometry. Results: Our results showed that NS knocking down inhibited proliferation and viability of K562 cells in a time-dependent manner. Cell cycle studies revealed that NS depletion resulted in G1 cell cycle arrest at short times of transfection (24 h) followed with apoptosis at longer times (48 and 72 h), suggest that post-G1 arrest apoptosis is occurred in K562 cells. Conclusion: Overall, these results point to essential role of NS in K562 cells, thus, this gene might be considered as a promising target for treatment of CML

Expression and Clinical Significance of IRE1-XBP1s, p62, and Caspase-3 in Colorectal Cancer Patients

Background: Three main cell signaling pathways including the endoplasmic reticulum stress (ERS) response, autophagy, and apoptosis play critical roles in both cell survival and death. They were found to crosstalk with one another during tumorigenesis and cancer progression. This study aimed to investigate the expression of the spliced form of X-box binding protein 1 (XBP1s), p62, and caspase-3, as the essential biomarkers of ERS, autophagy, and apoptosis in patients with colorectal cancer (CRC), as well as the correlation between their expression and clinicopathological data. Methods: This retrospective study was conducted on formalin-fixed paraffin-embedded (FFPE) blocks, which were collected from patients and their tumor margins, from the tumor bank of Imam Khomeini Hospital (Tehran, Iran) from 2017 to 2019. Tissue microarray (TMA) was used to measure the XBP1s, p62, and caspase-3 biomarkers. Data were analyzed using SPSS software version 20, and P≤0.05 was considered statistically significant. Results: Evaluating the total of 91 patients, a significant relationship was found between XBP1s expression and TNM stage (P=0.003), primary tumor (pT) (P=0.054), and the degree of differentiation (P=0.006); and between caspase-3 with pT (P=0.004), and lymphovascular invasion (P=0.02). However, no significant correlation was found between p62 and clinicopathological data. Furthermore, a positive relationship between XBP1s and p62 was confirmed (correlation coefficient: 22.2% and P=0.05).Conclusion: Our findings indicated that XBP1s could be considered as a target for therapy in personalized medicine

Study of CDH1 germline mutation in hereditary diffuse gastric cancer and lobular breast cancer: a multicenter study in Iran

Introduction: Mutations occurring in the CDH1 gene elevate the susceptibility to the development of hereditary diffuse gastric cancer (HDGC) as well as lobular breast cancer (LBC). LBCs with CDH1 germline mutations are classified as hereditary breast cancers, devoid of any indication of gastric carcinoma. As prophylactic gastrectomy is a recommended course of treatment for individuals with CDH1 mutations, it is advised that genetic testing be conducted for those who meet the criteria established by the National Comprehensive Cancer Network (NCCN). This study aimed to screen patients with HDGC for CDH1 testing and clinical management for the prevention of HDGC. Moreover, patients with LBC are tested for CDH1 mutation. Materials and Methods: In this multicenter study, thirty-one patients with HDGC were selected among 615 patients and admitted for CDH1 mutation testing. PCR for all 16 exons of CDH1 and Sanger sequencing were performed. Patients with LBC who are negative for BRCA1/2 were also included in this study regardless of gastric cancer history. Results: The results showed that 5.04% of patients with DGC were identified as HDGC of which 9.6% of individuals had a pathogenic CDH1 mutation and only 15.38% of cases with a family history carried germline mutation in CDH1. Furthermore, 7.6% of patients with LBC and negative for a family history of gastric cancer have CDH1 mutation. Discussion: All patients who met the NCCN criteria were not CDH1 mutation-positive, indicating other genes should be involved in DGC. Moreover, patients with LBC and negative for BRCA1/2 are recommended for testing the mutation in CDH1

The global, regional, and national burden of stomach cancer in 195 countries, 1990-2017 : a systematic analysis for the Global Burden of Disease study 2017

Background: Stomach cancer is a major health problem in many countries. Understanding the current burden of stomach cancer and the differential trends across various locations is essential for formulating effective preventive strategies. We report on the incidence, mortality, and disability-adjusted life-years (DALYs) due to stomach cancer in 195 countries and territories from 21 regions between 1990 and 2017. Methods: Estimates from GBD 2017 were used to analyse the incidence, mortality, and DALYs due to stomach cancer at the global, regional, and national levels. The rates were standardised to the GBD world population and reported per 100 000 population as age-standardised incidence rates, age-standardised death rates, and age-standardised DALY rates. All estimates were generated with 95% uncertainty intervals (UIs). Findings: In 2017, more than 1·22 million (95% UI 1·19–1·25) incident cases of stomach cancer occurred worldwide, and nearly 865 000 people (848 000–885 000) died of stomach cancer, contributing to 19·1 million (18·7–19·6) DALYs. The highest age-standardised incidence rates in 2017 were seen in the high-income Asia Pacific (29·5, 28·2–31·0 per 100 000 population) and east Asia (28·6, 27·3–30·0 per 100 000 population) regions, with nearly half of the global incident cases occurring in China. Compared with 1990, in 2017 more than 356 000 more incident cases of stomach cancer were estimated, leading to nearly 96 000 more deaths. Despite the increase in absolute numbers, the worldwide age-standardised rates of stomach cancer (incidence, deaths, and DALYs) have declined since 1990. The drop in the disease burden was associated with improved Socio-demographic Index. Globally, 38·2% (21·1–57·8) of the age-standardised DALYs were attributable to high-sodium diet in both sexes combined, and 24·5% (20·0–28·9) of the age-standardised DALYs were attributable to smoking in males. Interpretation: Our findings provide insight into the changing burden of stomach cancer, which is useful in planning local strategies and monitoring their progress. To this end, specific local strategies should be tailored to each country's risk factor profile. Beyond the current decline in age-standardised incidence and death rates, a decrease in the absolute number of cases and deaths will be possible if the burden in east Asia, where currently almost half of the incident cases and deaths occur, is further reduced. Funding: Bill & Melinda Gates Foundation

Revista de Ciências Médicas e Biológicas

Keywords: Klebsiella pneumoniae - ESBL strains- Plasmid profiling- Tehran Hospitals; Nosocomial infections- Drug resistance.Abstract: Local knowledge of antimicrobial susceptibilities of Klebsiella pneumoniae is important for implementation of effective hospitals anti-infective policies. One hundred isolates of K. pneumoniae collected from 3 different hospitals in Iran during 2004 were screened for their susceptibilities to thirteen different antibiotics using disk diffusion test and macro broth dilution assay. Isolates were then subjected to restriction endonuclease analysis of plasmid DNA. All isolates were susceptible to imipenem. The rates of resistance to other antibiotics were in the following order: amikacin (10%), piperacillin-tazobactam (%2), ciprofloxacin (20%), ceftizoxime (14%), cefexime (31%), ceftazidime (28%), cefotaxime (33%), nalidixic acid (32%), cephalexin (32%), gentamicin (30%), nitrofurantoin (31%) and piperacillin (66%). The production of extended spectrum betalactamase (ESBL) hydrolyzing ceftazidime and cefotaxime was detected in 54% of isolates. Of 100 isolates tested, 67 harbored plasmids and the remaining lacked any plasmid. Though the prevalence of ESBL phenotype in Iran is higher than western countries, it is close to figures reported from the region. Evidences for outbreaks with certain isolates of K. pneumoniae were found by restriction endonuclease analysis of plasmid DNA. This technique also showed the persistence of infections in the urinary tract of several patients.Salvado