The investigation of T-cell receptor subtypes in ovarian cancer: effects on survival and prognostic factors.

The aim of this study was to investigate T-cell receptor (TCR) changes in ovarian carcinoma (OC). The study included 24 malignant and 23 benign adnexal masses. DNA was isolated from ovarian samples. Multiplex PCR was used to determine T-cell gene clonality. PCR products were loaded onto polyacrylamide gel electrophoresis and imaged. The relationship between prognostic parameters and T-cell rearrangement was evaluated. In the study group (SG), TCRB-B positivity was higher than control group (CG) and TCRD receptor positivity was higher in CG. In SG, TCRG-B levels were higher in patients with stage I-II tumours compared to stage III. TCRG-B receptor was higher in patients with overall survival of 36 months and above. In our study, subgroups of TCRs were analysed in OC. According to our findings, significant differences in TCRB-B and TCRD subgroups may be applied to immune therapies. Understanding of TCR pathways will provide new treatment approaches in OC.IMPACT STATEMENTWhat is already known on this subject? Ovarian cancer is the most challenging kind of gynaecologic cancer. Although the main route of spread is direct invasion and peritoneal spread in the abdominal cavity, lymphatic invasion is also very important. Recent studies put forward that immunological mechanisms play crucial role in ovarian cancer. CD3 and CD8 positive lymphocyte infiltration in ovarian tumour is related with better prognosis where, FoxP3 positive lymphocyte infiltration is a predictor of poor survival. Also, immune checkpoints and inhibitors are important topics in ovarian cancer.What the results of this study add? Despite all the improvements and studies regarding immune system and ovarian cancer, the role T-cell receptor (TCR) subtypes is not clear and there are very few number of studies in this area. This is one of the first studies that describe the rearrangement of TCR subtypes between normal ovarian tissue and ovarian cancer tissue.What the implications are of these findings for clinical practice and/or further research? Understanding the role of TCR subtypes has a key role because studies about lymphocyte infiltration in ovarian cancer varies from region to region in the world and same type of lymphocytes has different effects in different studies. Further studies on TCR subtypes may elucidate us about the behaviour of lymphocytes. Additionally, these receptor may be targeted if their roles are better understood.

Examining the involvement of Slx5 in the apoptotic response to chronic activation of the spindle assembly checkpoint.

Microtubule-targeting agents represent one of the most successful groups of anticancer drugs used in cancer therapy today. These drugs induce a prolonged mitotic arrest through chronic spindle assembly checkpoint (SAC) activation. Apoptosis, an outcome of the prolonged mitotic arrest, is the main mechanism by which these anticancer drugs kill cancer cells. However, not much is known about the mechanism that directs chronic SAC activation to apoptosis among other possible outcomes. The aim of this study is to investigate whether Slx5, a sumo-targeted ubiquitin E3 ligase, is involved in directing chronic SAC activation to apoptosis. We show that chronic SAC activation triggered by a 10-h nocodazole incubation leads to a prolonged mitotic arrest in the slx5Δ strain similar to wild type (WT). However, the proportion of cells displaying apoptotic features such as nuclear fragmentation, DNA fragmentation, and reactive oxygen species (ROS) production were increased more in the WT strain during the chronic SAC activation compared to slx5Δ, indicating that Slx5 may be involved in the chronic SAC-activation-apoptosis relation. We also showed that the possible role of Slx5 in the chronic SAC activation-apoptosis association was not through ubiquitin dependent degradation of 3 apoptosis-related and sumoylated candidate proteins.

[Response With Methylphenidate to ADHD-Like Symptoms in Pervasive Developmental Disorder: Does CES-1 Enzyme Gene Polymorphism Have a Role?] / Yaygin Gelisimsel Bozukluklarda Dikkat Eksikligi Hiperaktivite Bozuklugu Semptomlarina Metilfenidatla Yetersiz Yanit: CES-1 Polimorfizminin Rolü Var mi?

OBJECTIVE: Methylphenidate is the first-choice medication for the Pervasive Developmental Disorders (PDDs), and comorbid Attention Deficit Hyperactivity Disorder (ADHD). But this approach generally results with poor outcomes, and increased adverse effects. It is aimed to investigate the comparison of cases who diagnosed with PDDs and Mild Mental Retardation (MR) and cases with pure ADHD in terms of the clinical response to MPH. Also we aimed to investigate the relations between CES-1 polymorphism gene and the clinical response to MPH. METHODS: For clarifying this we searched for three polymorphisms (Arg199/His, Ser75/Asn, and Ile49/Val) in carboxylesterase-1 gene (CES-1) in the saliva of patients diagnosed with PDD+ADHD. Also, we assessed the clinical response to MPH by dimensional approach using the Attention Deficit Hyperactivity Disorder Rating Scale IV and Clinical Global Impression-Improvement scale. RESULTS: PDD+ADHD groups had significantly higher Arg199/His polymorphism, and clinically responded poorer with symptoms sometimes even worsening to the MPH treatment compared with "pure" ADHD and ADHD+MR groups. CONCLUSION: This is the first study that an association between Arg199/His polymorphism in CES1 and altered treatment response to MPH in patients with PDD that presents with symptoms of ADHD.

Altered structural connectivity is related to attention deficit/hyperactivity subtypes: A DTI study.

This study aimed to provide novel insights into the white matter (WM) microstructural properties of Attention Deficit/Hyperactivity Disorder (ADHD) subtypes by recruiting a relatively large sample of stimulant-naïve children and adolescents who had no comorbidity other than Oppositional Defiant Disorder and were homogenous according to the DAT1 gene polymorphism. A sample of 72 ADHD subjects and 24 controls aged 8-15 years were enrolled in the study. We applied tract-based spatial statistics to the DTI measures for obtaining fractional anisotropy (FA) and axial, radial diffusivity (AD, RD) measures to explore ADHD type-related differences in WM for the whole brain. Comparing ADHD-Combined group (ADHD-C) with the ADHD predominantly inattentive group (ADHD-I) we detected increased RD in several bilateral brain area and increased AD mostly in left side of the brain, including the body and splenium of the corpus callosum; the anterior and posteriors limbs of the internal capsule; the superior, anterior and posterior corona radiata; the posterior thalamic radiation; and the superior longitudinal fasciculus. Likewise, mostly in the overlapping brain areas, the ADHD-C group presented increased AD values than ADHD-RI. Significant differences among ADHD types could be a preliminary evidence that they have distinct microstructural properties. There were no significant differences in diffusivity between controls and both the ADHD group as whole or any ADHD subgroups.

Decreasing ADHD phenotypic heterogeneity: searching for neurobiological underpinnings of the restrictive inattentive phenotype.

During the process of developing the DSM-5, a new phenotype of ADHD was proposed-the ADHD restrictive inattentive presentation (ADHD-RI), describing subjects with high endorsement of inattentive symptoms and a low level of hyperactivity. However, this phenotype was not included in the DSM-5 because of the lack of robust neurobiological data. We aimed to assess the specific neurobiological underpinnings of individuals presenting ADHD-RI. We compared a sample of 301 subjects (101 ADHD-Combined; 50 ADHD-RI; 50 ADHD predominantly inattentive type and 100 typically developing subjects) aged 8-15 years, using a complete neuropsychological battery, molecular genetic data (DRD4 and DAT1 most studied polymorphisms) and functional MRI during a Go-No/Go task. Subjects with ADHD-RI had a significantly different neuropsychological profile compared with the other groups, including lower psychomotor speeds, longer reaction times and the worst overall performance in the global neurocognitive index. The proportion of subjects with the presence of DRD4-7 repeat allele was significantly higher in ADHD-RI. The fMRI data suggested that more attention-related posterior brain regions (especially temporo-occipital areas) are activated in ADHD-RI during both Go and No-Go cues compared to TD controls and ADHD predominantly inattentive type. ADHD-RI may represent a different phenotype than other types of ADHD. In addition, our results suggest that reducing the phenotypic heterogeneity may aid in the search for the neurobiological underpinnings of ADHD.

Genistein-induced mir-23b expression inhibits the growth of breast cancer cells.

AIM OF THE STUDY: Genistein, an isoflavonoid, plays roles in the inhibition of protein tyrosine kinase phosphorylation, induction of apoptosis, and cell differentiation in breast cancer. This study aims to induce cellular stress by exposing genistein to determine alterations of miRNA expression profiles in MCF-7 cells. MATERIAL AND METHODS: XTT assay and trypan blue dye exclusion assays were performed to examine the cytotoxic effects of genistein treatment. Expressions of miRNAs were quantified using Real-Time Online RT-PCR. RESULTS: The IC50 dose of genistein was 175 µM in MCF-7 cell, line and the cytotoxic effect of genistein was detected after 48 hours. miR-23b was found to be up-regulated 56.69 fold following the treatment of genistein. It was found that miR-23b was upregulated for MCF-7 breast cancer cells after genistein treatment. CONCLUSIONS: Up-regulated ex-expression of miR-23b might be a putative biomarker for use in the therapy of breast cancer patients. miR-23b up-regulation might be important in terms of response to genistein.

Synergistic effect of ponatinib and epigallocatechin-3-gallate induces apoptosis in chronic myeloid leukemia cells through altering expressions of cell cycle regulatory genes.

PURPOSE: Ponatinib (P) has been used for the treatment of chronic myeloid leukemia (CML) and it is known that inhibition of BCR-ABL fusion protein by ponatinib induces apoptosis of CML cells. Epigallocatechin-3-gallate (EGCG), which is a polyphenol in green tea, induces apoptosis in different types of cancer cells. The purpose of this study was to determine the cytotoxic and apoptotic effects of ponatinib and EGCG combination in K562 CML cell line. This study also aimed to detect alterations of the expression levels of cell cycle-regulation related genes after ponatinib and EGCG combination in K562 CML cell line. METHODS: The cytotoxic effects of the compounds on K562 cells were determined in a time-and dose-dependent manner by using WST-1 analysis. The combination index (CI) isobologram was used to analyze the data. Apoptotic effects of P-EGCG were defined by flow cytometry and gene expressions were detected by RT-qPCR. RESULTS: IC50values of ponatinib and EGCG were 87.13 nM and 50µM, respectively. CI value of the P-EGCG was 0.658 and the combination showed synergistic effect (ED90 value: 28.39 nM ponatinib, 117.12 µg/ml EGCG). Ponatinib, EGCG and P-EGCG induced apoptosis compared to control cells. CyclinD1 and CDC25A were downregulated by P-EGCG by 2.49 and 2.63-fold, respectively. TGF-ß2 was upregulated by 4.57-fold. CONCLUSION: EGCG possesses cytotoxic and apoptotic properties and may cooperate with the growth inhibiting activity of ponatinib synergistically against CML cells. P-EGCG mediated apoptosis might be associated with upregulation of TGF-ß2 gene and downregulation of cyclinD1 and CDC25A genes.

Disodium pentaborate decahydrate (DPD) induced apoptosis by decreasing hTERT enzyme activity and disrupting F-actin organization of prostate cancer cells.

Animal and cell culture studies have showed that boron and its derivatives may be promising anticancer agents in prostate cancer treatment. Thus, DU145 cells were treated with disodium pentaborate decahydrate (DPD) for 24, 48, and 72 h in order to investigate the inhibitor effect and mechanisms of DPD. Then, cell proliferation, telomerase enzyme activity, actin polymerization, and apoptosis were detected by WST-1 assay, qRT-PCR, immunofluorescence labeling, and flow cytometry, respectively. We found that DPD inhibited the growth of human prostate cancer cell line DU145 at the concentration of 3.5 mM for 24 h. Our results demonstrated that 7 mM of DPD treatment prevented the telomerase enzyme activity at the rate of 38 %. Furthermore, DPD has an apoptotic effect on DU145 cells which were examined by labeling DNA breaks. With 7 mM of DPD treatment, 8, 14, and 41 % of apoptotic cells were detected for 24, 48, and 72 h, respectively. Additionally, immunofluorescence labeling showed that the normal organization of actin filaments was disrupted in DPD-exposed cells, which is accompanied by the alteration of cell shape and by apoptosis in targeted cells. Taken together, the results indicate that DPD may exert its cytotoxicity at least partly by interfering with the dynamic properties of actin polymerization and decreasing the telomerase activity. Eventually, for the first time, the results of this study showed that DPD suppressed the activity of telomerase in DU145 cells, and therefore, we suggested that DPD could be an important agent for its therapeutic potential in the treatment of prostate cancer.