Effects of bromodomain and extra-terminal inhibitor JQ1 and interleukin-6 on breast cancer cells.

BACKGROUND: Bromodomain and extra-terminal (BET) proteins are recognized acetylated lysine of histone 4 and act as scaffolds to recruit many other proteins to promoters and enhancers of active genes, especially at the super-enhancers of key genes, driving the transcription process and have been identified as potential therapeutic targets in breast cancer. However, the efficacy of BET inhibitors such as JQ1 in breast cancer therapy is impeded by interleukin-6 (IL-6) through an as-yet-defined mechanism. METHODS AND RESULTS: We investigated the interplay between IL-6 and JQ1 in MCF-7 and MDA-MB-231 human breast cancer cells. The results demonstrate that the efficacy of JQ1 on the inhibition of cell growth and apoptosis was stronger in MDA-MB-231 cells than in MCF-7 cells. Further, MCF-7 cells, but not MDA-MB-231 cells, exhibited increased expression of CXCR4 following IL-6 treatment. JQ1 significantly reduced CXCR4 surface expression in both cell lines and diminished the effects of IL-6 pre-treatment on MCF-7 cells. While IL-6 suppressed the extension of breast cancer stem cells in MCF-7 cells, JQ1 impeded its inhibitory effect. In MCF-7 cells JQ1 increased the number of senescent cells in a time-dependent manner. CONCLUSION: Analysis of gene expression indicated that JQ1 and IL-6 synergistically increase SNAIL expression and decrease c-MYC expression in MCF-7 cells. So, the BET proteins are promising, novel therapeutic targets in late-stage breast cancers. BET inhibitors similar to JQ1 show promise as therapeutic candidates for breast cancers, especially when triple-negative breast cancer cells are increased and/or tumor-promoting factors like IL-6 exist in the tumor microenvironment.

Immune checkpoints in targeted-immunotherapy of pancreatic cancer: New hope for clinical development.

Immunotherapy has been recently considered as a promising alternative for cancer treatment. Indeed, targeting of immune checkpoint (ICP) strategies have shown significant success in human malignancies. However, despite remarkable success of cancer immunotherapy in pancreatic cancer (PCa), many of the developed immunotherapy methods show poor therapeutic outcomes in PCa with no or few effective treatment options thus far. In this process, immunosuppression in the tumor microenvironment (TME) is found to be the main obstacle to the effectiveness of antitumor immune response induced by an immunotherapy method. In this paper, the latest findings on the ICPs, which mediate immunosuppression in the TME have been reviewed. In addition, different approaches for targeting ICPs in the TME of PCa have been discussed. This review has also synopsized the cutting-edge advances in the latest studies to clinical applications of ICP-targeted therapy in PCa.

Comparing the frequency of CD33+ pSTAT3+ myeloid-derived suppressor cells and IL-17+ lymphocytes in patients with prostate cancer and benign prostatic hyperplasia.

Prostate cancer (PCa) is one of the most epidemic types of cancer in men. The tumor microenvironment (TME) of PCa is involved in the emergence of immunosuppressive factors such as myeloid-derived suppressor cells (MDSC), which regulate the immune system by several mechanisms, including interleukin (IL)-10 production. On the other hand, IL-17+ helper T cells (Th17) induce MDSCs and chronic inflammation in TME by producing IL-17. This study demonstrated that the frequency of CD33+ pSTAT3+ MDSC and IL-17+ lymphocyte as well as IL-10 messenger RNA (mRNA) expression were significantly higher in the PCa patients than in the benign prostatic hyperplasia (BPH) group. Moreover, there was no significant relationship between the frequency of CD33+ pSTAT3+ MDSC, and IL-17+ lymphocyte with Gleason scores in the PCa group. We suggested that the higher frequency of CD33+ pSTAT3+ MDSC and IL-17+ lymphocyte and the more frequent expression of IL-10 mRNA in PCa patients may play roles in tumor progression from BPH to PCa.

The relation between the ghrelin receptor and FOXP3 in bladder cancer.

Immune responses play an important role in the fate of bladder cancer tumors. Treg cells are immunosuppressive and down-regulate the proliferation of effector T cells, which favor tumor survival. Ghrelin is a hormone that stimulates release of growth hormone and anti-inflammatory response to cancer cells. Ghrelin also is a gastrointestinal hormone that regulates immune responses via the growth hormone secretagogue receptor (GHS-R1a). The relation among ghrelin, its receptor, and Treg cells that surround bladder tumors is not clear. We found that Foxp3+ T and GHS-R1a cells are increased significantly in bladder tumor tissues. Therefore, we suggest that ghrelin may increase the number of Treg cells in the tumor and suppress activity of the immune system against bladder cancer.

Enhanced Frequency of CD19+IL-10+B Cells in Human Gastric Mucosa Infected by Helicobacter pylori.

BACKGROUND: CD19+IL-10+B cells are considered as a particular subset of immunosuppressive cells by producing interleukin 10 (IL-10), which plays an important role in infectious and autoimmune diseases. The aim of this study was to determine the number of CD19+IL-10+B cells in Helicobacter pylori (H. pylori) positive patients in comparison with H. pylori negative patients, and to determine the association with different clinical outcomes, such as gastritis and peptic ulcer disease (PUD), in infected patients. METHODS AND MATERIALS: We studied 25 infected patients with gastritis, 25 infected patients with PUD, and 25 patients negative for H. pylori. The number of CD19+IL-10+B cells was determined by immunofluorescence. RESULTS: The number of CD19+IL-10+B cells in patients infected with H. pylori was significantly 2.5-fold higher than uninfected patients (P < 0.0001). Also, the number of CD19+IL-10+B cells in infected patients with gastritis was significantly 1.45-fold elevated compared to infected patients with PUD (P = 0.001). CONCLUSIONS: These results demonstrate that the increased number of CD19+IL-10+B cells in infected patients and its association with other cells may play an important role in the pathogenesis of H. pylori infection.

Ghrelin induces autophagy and CXCR4 expression via the SIRT1/AMPK axis in lymphoblastic leukemia cell lines.

T cell acute lymphoblastic leukemia (T-ALL) is one of the most frequent malignancies in children, and the CXCR4 receptor plays an important role in the metastasis of this malignancy. Ghrelin is a hormone with various functions including stimulation of the release of growth hormone and autophagy in cancer cells. Moreover, SIRT1 and AMPK (AMP-activated protein kinase) stimulate expression of proteins involved in autophagy. On the other hand, autophagic cell death can be an alternative target for cancer therapy, in the absence of apoptosis. The relationship between ghrelin and the SIRT1/AMPK axis and the resulting effects on autophagy, apoptosis, proliferation, and expression of CXCR4 and the ghrelin receptor (GHS-R1a), in Jurkat and Molt-4 human lymphoblastic cell lines was not previously clear. Here we demonstrate that SIRT1 expression is upregulated during the induction of autophagy by ghrelin, an effect that is inhibited by inactivation of SIRT1/AMPK axis. In addition, ghrelin can affect CXCR4 and GHS-R1a expression. In conclusion, this work reveals that ghrelin induces autophagy, invasion, and downregulation of ghrelin receptor expression via the SIRT1/AMPK axis in lymphoblastic cell lines. However, in these cell lines ghrelin-induced autophagy does not lead to cell death due to weak induction of apoptosis.

Dietary behaviors in relation to prevalence of irritable bowel syndrome in adolescent girls.

BACKGROUNDS AND AIMS: There is limited evidence regarding the relationship between dietary behaviors and irritable bowel syndrome (IBS). This study aimed to explore the association between diet-related practices and prevalence of IBS. METHODS: The study was conducted among 988 adolescent girls living in Iran. Dietary behaviors were pre-defined and assessed in nine domains using a pre-tested questionnaire. To investigate the association between diet-related practices and the presence of IBS, this study used logistic regression analysis in crude and adjusted models. RESULTS: The prevalence of IBS was 16.9% in this population. Compared with individuals who did not consume fluid with their meal, those who always consumed fluid with meals had a greater chance of IBS (odds ratio [OR]: 2.91; P: 0.01). This study found a direct relationship between a greater intake of spicy food and IBS prevalence (OR: 5.28; P: 0.02). The individuals who ate fried foods every day also had a greater risk of IBS compared with those who did not consume fried foods (OR: 1.65; P: 0.01). The subjects who had lost ≥ 5 teeth had 2.23 times greater odds for IBS than the individual who had lost ≤ 1 tooth (OR: 2.23; P: 0.01) was a significant inverse relationship between the chewing sufficiency and the risk of IBS (OR: 4.04; P: 0.02). These associations remained significant after controlling for potential confounder. CONCLUSIONS: Intra-meal fluid intake, chewing insufficiency, higher tooth loss, and the consumption of spicy and fried food were associated with increased risk of IBS. Prospective studies are needed to confirm these findings.

Neuropsychological function in relation to dysmenorrhea in adolescents.

OBJECTIVE: Hormonal variations during the menstrual cycle may affect emotional regulation. We aimed to investigate the association between dysmenorrhea (the severe abdominal pain and cramps associated with menstruation) and cognitive abilities, emotional function and sleep patterns in adolescent girls. Moreover, we evaluated the frequency of premenstrual syndrome (PMS) in our population and then divided them into 4 groups: subjects with only PMS; subjects with only dysmenorrhea; individuals with both PMS and dysmenorrhea and normal subjects. STUDY DESIGN: In this cross sectional study, 897 adolescent girls who had entered menarche were recruited. Of these, 35.9% had only dysmenorrhea, 14.9% had only PMS, 32.7% had both PMS and dysmenorrhea while 16.5% had no PMS and/or dysmenorrhea (Normal). We assessed the tests for cognitive, emotional function and sleep patterns were compared for these groups. RESULTS: Individuals in the dysmenorrhea group had significantly higher depression, aggression, insomnia, daytime sleepiness and sleep apnea scores compared to normal controls and the PMS group, but did not have significantly different cognitive ability (P value <0.05). These differences were strongly correlated to pain intensity (P<0.001). However, there were no significant differences between those with only PMS and control subjects with regard to cognitive ability, emotional function and sleep pattern tests. CONCLUSIONS: Dysmenorrhea is highly prevalent among adolescents and appears to be associated with depressive mood, a tendency to aggressive behavior and sleep disorders among adolescent girls.