IL-25 Impact on Malignant B Cells Survival and T Cells Activation in Chronic Lymphocytic Leukemia.

T cell dysregulation and shift to T helper 2 responses, boosting tumor microenvironment support, contributes to the survival of leukemic B cells in Chronic Lymphocytic Leukemia. Interleukin (IL)-25 is involved in the initiation of T helper 2 cell responses. Signal transduction of IL-25 begins with the heterodimer receptor (IL-17RA/IL-17RB). The presence of IL-25 in the tumor microenvironment may affect the supportive effects of T cells in the surrounding tumor cell environment. The purpose of this study was to evaluate the role of IL-25 in the biology of CLL. IL-17RB expression in CD3+ and CD19+ cells was assessed in isolated peripheral blood mononuclear cells (PBMCs) of nine CLL patients and nine healthy subjects by real-time polymerase chain reaction and flow cytometry. B cells were positively enriched from PBMCs using magnetic-activated cell sorting (MACS). PBMCs and purified leukemic B cells were cultured with recombinant human IL-25 (20ng/ml) for 72 hours, then the viability and apoptosis of cultured cells were measured by MTT assay and AnnexinV/7AAD. Furthermore, the levels of CD69 expression on T lymphocytes and IL-17RB in T and B cells were determined by flow cytometry. The basal level of IL-17RB expression in CLL patients was significantly higher than that in control individuals. In addition, the percentage of IL-17RB+/CD3+, IL-17RB+/CD19+ cells and CD69+/CD3+ cells increased after 72 hours of culture with IL-25 in CLL patients compared to healthy subjects. IL-25 also reduces the apoptosis rate of tumor cells. We found that IL-25 could stimulate T cells in CLL patients and lower B cell death. This suggests that IL-25 might have a role in enhancing the survival of tumor cell by expressing receptors for inflammation, such as IL-17RB, and might be involved in the development of CLL.

Anti-TPO antibody and thyroid hormone levels in Iranian female breast cancer patients and their association with prognostic factors: a case-control study.

The aim of this study was to assess prevalence of anti-thyroid peroxidase (anti-TPO) antibody and thyroid hormones in Iranian female breast cancer patients, compare them to a control population, and investigate their association with prognostic factors. In this case-control study, breast cancer patients were selected from a surgery clinic in a tertiary hospital and control group participants were enrolled from those who had visited for mammography screening. Participants with any history of thyroid disease, or thyroid related medication were excluded from both groups. Groups were assessed for levels of thyroid stimulating hormone (TSH), T3, T4, and anti-TPO. In addition, the status of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) was determined for cancer patients. Overall 69 participants (39 cancer patients and 30 controls) were included. Difference in serum anti-TPO levels between the two groups was not statistically significant (p-value: 0.184). While a significant difference was observed for T4 and TSH levels between groups (p-value: 0.034 and <0.001, respectively), T3 levels did not reveal any significant difference (p-value: 0.177). In addition, ER, PR, and HER2 status were not correlated with anti-TPO levels. This results can serve as preliminary evidence that thyroid autoimmunity is not correlated with breast cancer incidence in Iranian female population. However, additional studies with larger sample sizes are required for more conclusive evidence.

Anti-tumor effect of berberine on chronic lymphocytic leukemia cells.

Chronic lymphocytic leukemia (CLL) is a blood malignancy that is characterized by remarkable expression of CD69 and Ki67 in CLL cells. Elevated levels of Cleaved-Poly (ADP-ribose) polymerase-1 (PARP1) and microRNA-155 (MiR-155) are related to poor prognosis of disease. Berberine as a natural isoquinoline alkaloid, has shown an anti-tumor potential in tumor cells. The objective of present study was to explore some aspects of molecular mechanisms of berberine effect in CLL cells. To analyze the expression of CD69 and Ki67 using flow cytometry, 16 peripheral blood samples and seven bone marrow aspirates were collected from CLL patients. Isolated peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) were treated with 25 µM of berberine for 24 h. The level of miR-155 expression was subsequently evaluated by real-time PCR. Furthermore, western blot was used for assessment of cleaved PARP1. Our results demonstrated a significant reduction in CD69 and Ki67 expression on CD19+ cells when the cells were treated by berberine. Interestingly, the expression level of miR-155 was reduced after berberine treatment in compare to the control group. Furthermore, western blotting revealed an increased level of cleaved PARP1 in dose-dependently manner in CLL cells. The results confirmed the anti-tumor impact of berberine on CLL cells through reducing CD69, Ki67, and miR-155 expression and increasing cleaved PARP1 may be considered as an option for future clinical studies.

Effectiveness of crocin of saffron (Crocus sativus L.) against chemotherapy-induced peripheral neuropathy: A randomized, double-blind, placebo-controlled clinical trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the complications vexes patients treated with anti-cancer agents. Saffron has been demonstrated to attenuate symptoms of peripheral neuropathy in animal models. Also, there is a published clinical trial that investigated the pain relieving effect of saffron following nationally accepted rules and concluded that saffron was successful in alleviating pain symptoms in patients suffering from fibromyalgia. AIM OF THE STUDY: We aimed to determine the efficacy of crocin as a constituent of saffron in CIPN as the first report. MATERIALS AND METHODS: One hundred and seventy-seven enrolled eligible patients (between December 2018 and March 2020) for study entry were cases demonstrating mild to severe symptomatic CIPN for at least a month. These cases were randomly assigned to two main groups including 15 mg crocin tablet, bid (30 mg total daily target dose) and placebo tablet for 8 weeks. A crossover study was performed with a 2-week washout period. Patient outcomes were measured once a week for 8 consecutive weeks. RESULTS: Grade of sensory, motor and neuropathic pain decreased considerably and significantly in the crocin group compared with placebo (P < 0.05). Observed toxicities were mild and adverse effects had no significant differences between the two groups (P > 0.05). CONCLUSIONS: Crocin considerably seems to be effective for relieving symptoms of CIPN in cancer patients receiving chemotherapy agents. However, further studies are needed about crocin with its beneficial neuropharmacological effects and lower adverse effects than the chemical agents such as antidepressants, lamotrigine, and gabapentin.

Apoptotic effect of berberine via Bcl-2, ROR1, and mir-21 in patients with B-chronic lymphocytic leukemia.

Berberine is a natural isoquinoline alkaloid that has been shown to inhibit the proliferation and induce apoptosis in a wide variety of tumor cells. However, the action mechanism of berberine in CLL cells is unknown. The previous study has shown that berberine leads to reduced viability and elevated levels of apoptosis in PBMCs of CLL patients. CLL cells are characterized by remarkable expression of Bcl-2 and ROR1 which leads to activation and survival and increases disease progression in patients. High-level expression of miR-21 in patients with CLL is associated with a higher risk of death. Here we investigated the anticancer effects of berberine upon peripheral blood mononuclear cells (PBMCs) of CLL patients. To evaluate the expression of anti-apoptotic proteins and ROR1 using flow cytometry and western blot, PBMCs were treated with 25 µM of berberine for 24 hr. The expression levels of mir-21 were evaluated by real-time PCR. Examination of treated cells demonstrated that berberine decreased Bcl-2 and ROR1 levels. Although western blot results did not show any change in Bax as a pro-apoptotic protein, an increased Bax/Bcl-2 ratio indicated that mitochondrial pathway is involved in berberine-induced apoptosis of CLL cells. Interestingly, berberine could reduce the expression of miR-21 in comparison to the untreated group. Our findings describe some of the molecular mechanisms of berberine by decreasing Bcl-2, ROR1, and mir-21 which may be considered as a novel apoptosis inducer in CLL cells.

IL-27 impact on NK cells activity: Implication for a robust anti-tumor response in chronic lymphocytic leukemia.

Interleukin 27 (IL-27) belongs to IL-12 cytokine family, has shown anti-tumor potential in several solid tumors, as well as hematologic malignancies. IL-27 can inhibit tumor growth and progression through direct and indirect mechanisms, such as inhibition of proliferation, angiogenesis, induction of apoptosis in tumor cells, and anti-tumor immune response. B-CLL is characterized by remarkable immune perturbation, which leads to disease complications and reduced effectiveness of the treatment. Natural killer cells (NK) are considered as an important arm for the elimination of transformed cells. However, NK cells have shown significant impairment in patients with CLL. Here we analyzed the activity of recombinant human (rh) IL-27-stimulated NK cells in bone marrow (BM) and peripheral blood (PB) of CLL patients using cell surface flow cytometry assessment, and cytotoxicity assay. We showed that rhIL-27 can increase CD69 on NK cells both in BM and PB. Interestingly, BM-NK cells treated with rhIL-27 exhibited a significant increase in degranulation and NK cell-mediated cytotoxicity as compared with untreated NK cells, whereas it did not improve NK cell activity of PB. These observations added further explanation to the anti-tumor activity of IL-27 and also could pave the way to adoption immunostimulatory adjuvant for therapies in CLL.

Evaluation of the Protective Effect of Cystone Against Cisplatin-induced Nephrotoxicity in Patients with Cancer: A Pilot Study.

INTRODUCTION: Cisplatin is a widely used anti-cancer drug that is commonly administered for the treatment of various cancers. However, nephrotoxicity is the most important side effect of this drug which limits its use. This study aimed to investigate the protective effect of Cystone against nephrotoxicity induced by Cisplatin in patients with cancer. METHODS: This pilot clinical trial study was conducted on 43 cancer patients treated with Cisplatin (75 mg/m2 for a period of six months). The subjects were divided into treatment group (receiving Cystone, two per 8 hours; n = 21) and control group (n = 22). The two groups were compared with each other in terms of demographic and laboratory variables. RESULTS: In the intervention group receiving Cystone, serum creatinine-based GFR level (P = 0.453) and 24-hour urine creatinine-based GFR level (P = 0.397) did not change significantly during the studied period, but in the control group, serum creatinine-based GFR level (P = 0.013) and 24-hour urine creatinine-based GFR level (P = 0.016) significantly changed. Serum creatinine-based GFR level increased by 2.3 units in the intervention group and 10.5 units in the control group (P = 0.005) in the six months of the study. At the end of the sixth month, 24-hour urine creatinine-based GFR level increased by 2.2 units in the intervention group and 0.8 unit in the control group (P = 0.008). CONCLUSIONS: The use of Cystone resulted in more stable kidney function indices in the intervention group, as compared with the control group. Therefore, Cystone seems to have a protective effect against nephrotoxicity induced by Cisplatin in cancer patients.

Association between mean platelet volume and severity of rheumatoid arthritis.

INTRODUCTION: In recent years, it is suggested that platelet histogram indices, such as mean platelet volume (MPV) may be related to the activity of rheumatoid arthritis (RA). The aim of this study was to assess relationship between MPV and activity of rheumatoid arthritis. METHODS: Sixty consecutive patients fulfilling the American College of Rheumatology (ACR) criteria for RA were recruited from the rheumatology outpatient clinics in Semnan, Iran. Current disease activity score (DAS-28 score) was assessed at baseline, 2 months and 4 months after the admission time and beginning of the treatment schedule. Complete blood count (including MPV), C-reactive protein (CRP) and ESR were measured in each visit. MPV was analyzed by the Cell Dyne 3500 automated blood cell counter. RESULTS: There was a significant reduction in DAS-28 score within 4 months of total assessment (from 4.47 ± 2.24 versus 3.18 ± 1.55) (p < 0.001). There was no significant difference in MPV levels at the three study time points. No significant correlations were observed between the DAS-28 score and mean MPV levels at the same time points. The rate of positive CRP was decreased within the same period (p = 0.002); however, the trend of the changes in other laboratory parameters including MPV, platelet count and ESR values was not significant. The measurement of MPV value did not correlate with disease activity in RA patients within 4 months of treatment scheduling. CONCLUSION: Although therapeutic regimens, which improve RA manifestations, can reduce RA activity, they had no effect on MPV during this time period. It seems MPV may not be able to predict disease activity in RA patients.

The Valuable Role of Measuring Serum Lipid Profile in Cancer Progression.

OBJECTIVE: Serum lipid levels are not only associated with etiology, but also with prognosis in cancer. To investigate this issue further, we aimed to evaluate the serum levels of lipids in association with the most important prognostic indicators in cancer patients at the start of chemotherapy. METHODS: In a retrospective cross-sectional study, using existing medical records obtained from 2009-2014, the data of all incident cancer cases in Iranian patients referred to the Semnan oncology clinic for chemotherapy were analyzed. Data on demographics, cancer type, prognostic indicators (e.g. lymph node involvement, metastasis, and stage of disease), as well as the patient's lipid profile were collected. We used multiple logistic regression models to show the relationship between prognosis indicators and lipid profile adjusting for age, gender, and type of cancer. RESULTS: The data of 205 patients was gathered. We found a significant difference in the lipid profile between different types of cancers (breast, colon, gastric, and ovarian). With the exception of high-density lipoprotein levels in women, which were higher than in men, the means of other lipid profiles were similar between the genders. There was a significant association between higher levels of low-density lipoprotein (LDL >110mg/dL) in the serum and metastasis (adjusted odds ratio=2.4, 95% CI 1.2-3.5). No significant association was reported between lipid profile and lymph nodes involvement and stage of the disease. CONCLUSION: Our study suggested a benefit of measuring serum levels of lipids for predicting cancer progression. Increased LDL levels can be considered a predictive factor for increasing the risk of metastasis.

Effects of cigarette smoking on morphological features of platelets in healthy men.

OBJECTIVES: To assess the effects of cigarette smoking on thrombocytopoiesis and some platelet morphological parameters in healthy male smokers. METHODS: In this cross-sectional study, 542 consecutive healthy men (aged 20 to 88 years), referred to the laboratory of Fatemieh Hospital, Semnan, Iran, between November 2011 and November 2012 for checking up were enrolled. The subjects were divided into 2 groups of smokers (n=258 with frequency of 10 or more cigarette per day with more than 12 months duration of smoking) and non-smokers (n=284). The blood samples were extracted to examine values of platelet indices using an ABX Micros 60 cell counter. RESULTS: Comparing platelet indices across smokers and non-smokers showed that the mean platelet count was statistically significantly higher in adult smokers than in nonsmokers (264.1 ± 81.2/µl versus 247.7 ± 83.9/µl, p=0.021), while the mean plateletcrit value was contrarily lower in the adult smokers (18.0 ± 12.0% versus 25.0 ± 10.0%, p less than 0.001). Other platelet indicators were not discrepant between the smokers and non-smokers. CONCLUSION: Cigarette smoking in healthy individuals results in significant and considerable effects on platelet morphological indices. The mean platelet count is significantly increased, and plateletcrit values are reduced, compared with non-smoking status.

Knowledge and attitude toward evidence-based medicine among medical students in Semnan, Iran.

OBJECTIVES: Evidence-based medicine (EBM) has gained widespread acceptance in medicine. Little is known about the attitudes, knowledge, and behavior of medical students toward EBM in developing countries. This study was designed to assess medical students' awareness and attitudes toward EBM and to obtain the basis required for developing appropriate teaching and learning opportunities. METHODS: This was a cross-sectional study in which medical students completed a questionnaire to determine their attitudes, knowledge, and perceptions regarding EBM. RESULTS: Completed questionnaires were received from 84% (143) of 170 medical students. Only 24.5% of respondents had good basic information and familiarity with the term of EBM. The majority (89.3%) of participants had positive attitude toward EBM and agreed that it was useful in the management of patients. Mostly were interested in learning the skills of EBM. Most of the respondents (80.2%) had no or little awareness of EBM resources especially the Cochrane, DARE, and Bandolier clinical evidence database. Forty-two (29%) reported having had formal training in search strategies. Most of the respondents did not understand but would like to learn about technical terms used in EBM, and about a third felt able to explain to others the meaning of some of these terms. CONCLUSIONS: This study demonstrates lack of adequate knowledge about basic concepts of EBM among medical student. On the other hands, there is an overall positive attitude toward EBM. There is need for educational interventions and incorporating formal teaching of EBM at medical education.

The relationship between mean platelet volume and severity of acute ischemic brain stroke.

OBJECTIVE: To determine whether an association exists between mean platelet volume (MPV) and severity of acute ischemic stroke. Also, to investigate the power of MPV for discriminating more severe ischemic stroke from mild events. METHODS: We divided 100 patients with first ischemic stroke presenting to the Neurology Department, Fatemieh Hospital, Semnan, Iran between January 2010 and January 2011 into 2 groups based on Rankin score (group 1: score 0-2, and group 2: score 3 or more). Blood samples were taken to measure MPV. Severity of ischemic stroke was assessed by the Modified Rankin scale. RESULTS: The MPV value was higher and more significant in group 2 than group 1 (9.36+/-0.95 versus 8.55+/-0.65, p<0.001). Also, the mean platelet count was significantly lower in group 2 (238.8+/-89.2 versus 283.7+/-59.2, p=0.020). After controlling for the risk profile associated with ischemic stroke in the multivariate logistic regression model, the effect of MPV in ischemic stroke remained statistically significant (p=0.012). The area under the ROC curve was 0.77, indicating the high discriminative value of MPV for predicting severe ischemic stroke based on Rankin score >/= 3 from mild stroke. CONCLUSION: The MPV is associated with ischemic stroke severity and has a high value for discriminating severe from mild ischemic stroke.