Distinct tumor-TAM interactions in IDH-stratified glioma microenvironments unveiled by single-cell and spatial transcriptomics.

Tumor-associated macrophages (TAMs) residing in the tumor microenvironment (TME) are characterized by their pivotal roles in tumor progression, antitumor immunity, and TME remodeling. However, a thorough comparative characterization of tumor-TAM crosstalk across IDH-defined categories of glioma remains elusive, likely contributing to mixed outcomes in clinical trials. We delineated the phenotypic heterogeneity of TAMs across IDH-stratified gliomas. Notably, two TAM subsets with a mesenchymal phenotype were enriched in IDH-WT glioblastoma (GBM) and correlated with poorer patient survival and reduced response to anti-PD-1 immune checkpoint inhibitor (ICI). We proposed SLAMF9 receptor as a potential therapeutic target. Inference of gene regulatory networks identified PPARG, ELK1, and MXI1 as master transcription factors of mesenchymal BMD-TAMs. Our analyses of reciprocal tumor-TAM interactions revealed distinct crosstalk in IDH-WT tumors, including ANXA1-FPR1/3, FN1-ITGAVB1, VEGFA-NRP1, and TNFSF12-TNFRSF12A with known contribution to immunosuppression, tumor proliferation, invasion and TAM recruitment. Spatially resolved transcriptomics further elucidated the architectural organization of highlighted communications. Furthermore, we demonstrated significant upregulation of ANXA1, FN1, NRP1, and TNFRSF12A genes in IDH-WT tumors using bulk RNA-seq and RT-qPCR. Longitudinal expression analysis of candidate genes revealed no difference between primary and recurrent tumors indicating that the interactive network of malignant states with TAMs does not drastically change upon recurrence. Collectively, our study offers insights into the unique cellular composition and communication of TAMs in glioma TME, revealing novel vulnerabilities for therapeutic interventions in IDH-WT GBM.

CRISPR-Based Fluorescent Reporter (CBFR) Assay for Sensitive, Specific, Inexpensive, and Visual Detection of a Specific EGFR Exon 19 Deletion in NSCLC.

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein receptor with intracellular tyrosine kinase activity. Mutations in the EGFR gene, including deletions in exon 19 and the mutation L858R, induce responsiveness of non-small cell lung cancer (NSCLC) to a group of drugs known as tyrosine kinase inhibitors. Here, we report the development of the CRISPR-based fluorescent reporter (CBFR) assay including a two-step strategy combining PCR amplification and Cas12a-driven cleavage to detect the delE746_A750 subtype of EGFR exon 19 deletions. Sensitivity and specificity of the CBFR assay were analyzed with different concentrations of fluorescence reporter and different amounts of PCR product. The results demonstrated that increasing the fluorescent reporter to 4 µM and the PCR product to 5 µl enhanced sensitivity. The CBFR assay could detect EGFR exon 19 deletion even with a frequency of 1% in samples. In clinical NSCLC samples, optimized CBFR assay enabled visual detection of the delE746_A750 subtype in less than 1 h. The CBFR assay provides a sensitive, specific, and simple strategy designed based on a straightforward and inexpensive process. We suggest that the CBFR assay could serve as a diagnostic approach to detect mutations, deletions, and pathogens in underequipped laboratories and promote personalized therapeutic approaches.

Data mining of bulk and single-cell RNA sequencing introduces OBI1-AS1 as an astrocyte marker with possible role in glioma recurrence and progression.

Long non-coding RNAs (LncRNAs) are widely known for their various functions in cancer from tumor initiation to tumor progression and metastasis. Gliomas are the most prevalent primary forms of brain tumor, classified into grades I to IV according to their malignant histological features with grade IV, also known as glioblastoma multiforme (GBM), displaying the highest level of malignancy. Thus, the search for differentially expressed LncRNAs in GBM versus low-grade glioma to uncover new insights into the molecular mechanisms of glioma progression have intensified. Bulk RNA sequencing pinpointed decreased expression of OBI1-AS1 in GBM compared to low-grade glioma samples. Subsequent single nuclei RNA sequencing revealed OBI1-AS1 to be a super-exclusive astrocyte marker with AUC = 0.99 and the potential to fully differentiate astrocytes from other brain cell types. Additional supplementary bioinformatics analysis exhibited OBI1-AS1 role in synaptic signal transduction and glutamatergic signaling. In addition, ChIP-Seq data were analyzed to explore transcription factors that can regulate OBI1-AS1 expression in neural cells. Results of Hi-C, methylation and ChIP-Seq analysis strongly suggest methylation of the CTCF binding site serving a central role in regulation of OBI1-AS1 expression via managing chromatin interactions. Our study indicated that lncRNAs, like OBI1-AS1, could be extremely precise in identifying the astrocyte cluster in the single-cell transcriptome and demonstrating superiority to well-established astrocyte markers such as GFAP, S100B, ALDH1L1, and AQP4.

Differential Expression of Hypoxia-Related Genes in Primary Brain Tumors and Correlation with Clinicopathologic Data.

OBJECTIVE: Meningiomas and gliomas are common benign and malignant primary brain tumors, respectively. One of the most prominent features of aggressive malignancies contributing to their progression is their ability to cope with hypoxia. Therefore, glioma tumors are expected to better cope with adverse hypoxic conditions and, consequently, display significantly different expression levels of hypoxia-adaptive genes. METHODS: Thirty-three glioma (17 glioblastoma multiforme [GBM], 16 low-grade glioma [LGG]) and 32 meningioma samples were investigated for expression of hypoxia adaptation- related genes by real-time polymerase chain reaction. The same investigation was carried out for GBM, the most malignant form of glioma, versus LGG. The findings were further checked by bioinformatics analysis of expression levels using RNA-seq data. Additional investigations conducted include receiver operating characteristic curve analysis to assess the power for each gene in differential diagnosis of glioma from meningioma. RESULTS: A greater level of hypoxia-inducible factor (HIF) 1α expression in glioma samples compared with meningioma and greater expression levels of Yes-associated protein (YAP) 1 and G-protein-coupled receptor class C group 5 member A (GPRC5A) in meningioma were observed, with P values 0.0005, <0.0001, and <0.0001 for GPRC5A, HIF1α, and YAP1, respectively. Comparison of GBM with LGG also revealed GPRC5A to have significantly greater expression in GBM with P = 0.0381. The calculated area under the curve was 0.7536, 0.8438, and 0.8272 for GPRC5A, HIF1α, and YAP1, respectively, which represented acceptable power for these genes in differential diagnosis of glioma tumor types from meningioma and tumor subtypes GBM from LGG under study. CONCLUSIONS: These results imply that these genes can possibly be implicated in brain tumor hypoxia-adaptation response with tumor-specific roles and patterns of expression.

Decreased Sox2 Messenger RNA Expression in Basal Cell Carcinoma.

BACKGROUND: Sox2, zeb1, and p21 have been implicated in aggressive behavior of squamous cell carcinoma (SCC) and melanoma. However, their expression level in basal cell carcinoma (BCC) has not been elucidated. We hypothesized BCC, contrary to SCC, and melanoma, could be a suitable model to study mechanisms which attenuate tumor metastasis. The aim of this study was to examine the messenger RNA (mRNA) expression levels of sox2, zeb1, and p21 in BCC. MATERIALS AND METHODS: Twenty-seven nonmetastatic BCC and twelve normal skin samples were evaluated using real-time reverse transcriptase polymerase chain reaction. RESULTS: The stemness marker sox2 demonstrated marked down-regulation, but zeb1 and p21 showed no significant change. CONCLUSIONS: Here, we report a negative association between sox2 mRNA expression level and nonmetastatic BCC, thus, providing a likely explanation for the fact that normal skin is more reliant on sox2 than BCC. BCC may be using decreased sox2 mRNA to remain incognito from metastatic potential.

Detection of CCND1 , C-MYC , and FGFR1 amplification using modified SYBR Green qPCR and FISH in breast cancer

Background/aim: The aims of this study were to detect CCND1 , C-MYC , and FGFR1 amplification using qPCR, confirmation with FISH, and to further assess their clinicopathological relevance. Materials and methods: Thirty-five breast tumor samples were analyzed for amplification of the selected genes using modified SYBR Green qPCR. The accuracy of the qPCR was assessed by FISH as a gold-standard method. Results: CCND1 , C-MYC , and FGFR1 amplifications were observed in 34.28%, 28.57%, and 17.14% of the 35 samples, respectively. qPCR results were significantly confirmed by FISH and qPCR and FISH showed excellent correlation (P = 0.000). CCND1 amplification with tumor stage (P = 0.044), positive metastatic status (P = 0.042), positive family history (P = 0.042), and C-MYC status (P = 0.005); C-MYC amplification with tumor size (P = 0.021), tumor grade (P = 0.018), tumor stage (P = 0.032), and FGFR1 status (P < 0.000); and FGFR1 amplification with tumor size (P = 0.041) and positive ER status (P = 0.042) were statistically associated. Conclusion: Our findings revealed that the applied qPCR approach could precisely quantify the relative gene copy number. More studies with a larger sample size are suggested to confirm the clinicopathological value of CCND1 , C-MYC , and FGFR1 amplification.

Comparison of Oral Lichen Planus and Systemic Lupus Erythematosus in Interleukins Level.

Lichen planus (LP) is a chronic inflammatory mucocutaneous disorder with unknown etiology. Systemic lupus erythematosus (SLE) is known as a prototypic autoimmune disease. Cytokines play a key role in the pathogenesis of both diseases. Various cytokines, such as interleukin 6 (IL-6), interleukin 10 (IL-10), interferon alpha (INF-a), and Tumor Necrosis Factor-alpha (TNF-a) can serve as biomarkers to predict SLE severity and monitor disease activity. In this review, we compare interleukins in oral lichen planus and lupus erythematosus as an autoimmune disease prototype. So, this review may provide insight for researchers in completing the cytokine network in OLP. Among the etiologic factors, the imbalance between Th-1 and Th-2 cytokine production plays an important role in the development of both diseases. By understanding cytokines and immunoregulatory networks of cytokines in these patients, appropriate treatment can be offered. There are many limitations in cytokine studies, which we have described in this article.

A Placebo-Controlled Study of Raloxifene Added to Risperidone in Men with Chronic Schizophrenia.

Selective estrogen receptor modulators (SERMs) such as raloxifene have already shown beneficial effects on negative, positive and general psychopathology symptoms in postmenopausal women with schizophrenia. The purpose of the present investigation was to assess the efficacy of raloxifene as an adjuvant agent in the treatment of men with chronic schizophrenia in an 8-week double-blind and placebo-controlled trial. In a randomized, double-blind and placebo-controlled study, forty-six male patients diagnosed with schizophrenia (DSM-IV-TR), were randomized to either raloxifene (120 mg/day) or placebo in addition to risperidone (6 mg/day) for eight weeks. The assessment was performed using the positive and negative symptom scale (PANSS) at baseline, and at weeks 2, 4, 6 and 8. Extrapyramidal symptom rating scale (ESRS) at baseline, weeks 1, 2, 4, 6, 8 and Hamilton depression rating scale (HDRS) at baseline and week 8 were also used to assess extrapyramidal symptoms and depression simultaneously. Forty-two patients completed the trial. The raloxifene group showed significantly greater improvement on the negative subscale (P<0.001), the general psychopathology subscale (P=0.002) and total PANSS score (P<0.001) in comparison to the placebo group at the endpoint. There was no significant difference in the reduction of positive symptoms score between the two group (P=0.525). Extrapyramidal symptom rating scale and Hamilton depression rating scale and frequency of other adverse effects were comparable between two groups.This study indicates raloxifene as a potential adjunctive treatment strategy for chronic schizophrenia in men.

Lactobacillus acidophilus and Lactobacillus crispatus culture supernatants downregulate expression of cancer-testis genes in the MDA-MB-231 cell line.

Lactobacilli are probiotics shown to have antitumor activities. In addition, they can regulate gene expression through epigenetic mechanisms. In this study, we aimed to assess anti tumor activities of Lactobacillus acidophilus and Lactobacillus crispatus on the MDA-MB-231 breast cancer cell line. The effects of culture supernatants were determined by MTT [3-(4,5-dimethylthiazol-2-y-2,5-diphenyltetrazolium bromide] assay. Changes in expression of 5 cancer-testis antigens (CTAs), namely AKAP4, ODF4, PIWIL2, RHOXF2 and TSGA10 ,were analyzed by quantitative real time RT-PCR. The culture supernatants of the 2 lactobacilli inhibited MDA-MB-231 cell proliferation. In addition, transcriptional activity of all mentioned CTAs except AKAP4 was significantly decreased after 24 hour treatment with culture supernatants. This study shows that Lactobacillus acidophilus and Lactobacillus crispatus have antiproliferative activity against MDA-MB-231 cells. In addition, these lactobacilli could decrease transcriptional activity of 4 CTAs. Previous studies have shown that expression of CTAs is epigenetically regulated, so it is possible that lactobacilli cause this expression downregulation through epigenetic mechanisms. As expression of CTAs in cancers is usually associated with higher grades and poor prognosis, downregulation of their expression by lactobacilli may have clinical implications.

BMI1 and TWIST1 downregulated mRNA expression in basal cell carcinoma.

BACKGROUND: BMI1, TWIST1 and SNAI2/SLUG have been implicated in aggressive behavior of squamous cell carcinoma (SCC) and melanoma and BMI1 expression could identify subtypes of Merkel cell carcinoma (MCC). However, BMI1, TWIST1 and SNAI2 expression levels in basal cell carcinomas (BCCs) have not been elucidated. We hypothesized BCC could be a good model system to decipher mechanisms which inhibit processes that drive tumor metastasis. The aim of this study was to examine the mRNA expression level of BMI1, TWIST1, and SNAI2 in BCCs. MATERIALS AND METHODS: Thirty-five fresh non-metastatic BCC tissue samples and seven fresh normal skin tissue samples were evaluated by real-time RT-PCR. RESULTS: BMI1 and TWIST1 demonstrated marked down-regulation (p<0.00l, p=0.00l respectively), but SNAI2 showed no significant change (p=0.12). CONCLUSIONS: Previous literature has clearly demonstrated a positive association between BMI1 and TWIST1 expression and metastatic BCC, aggressive SCC and melanoma. Here, we demonstrated a negative association between BMI1 and TWIST1 mRNA expression level and BCC.

Mercury specifically induces LINE-1 activity in a human neuroblastoma cell line.

L1 retro-elements comprise 17% of the human genome. Approximately 100 copies of these autonomous mobile elements are active in our DNA and can cause mutations, gene disruptions, and genomic instability. Therefore, human cells control the activities of L1 elements, in order to prevent their deleterious effects through different mechanisms. However, some toxic agents increase the retrotransposition activity of L1 elements in somatic cells. In order to identify specific effects of neurotoxic metals on L1 activity in neuronal cells, we studied the effects of mercury and cobalt on L1-retroelement activity by measuring levels of cellular transcription, protein expression, and genomic retrotransposition in a neuroblastoma cell line compared with the effects in three non-neuronal cell lines. Our results show that mercury increased the expression of L1 RNA, the activity of the L1 5'UTR, and L1 retrotransposition exclusively in the neuroblastoma cell line but not in non-neuronal cell lines. However, cobalt increased the expression of L1 RNA in neuroblastoma cells, HeLa cells, and wild-type human fibroblasts, and also increased the activity of the L1 5'UTR as well as the SV40 promoter in HeLa cells but not in neuroblastoma cells. Exposure to cobalt did not result in increased retrotransposition activity in HeLa cells or neuroblastoma cells. We conclude that non-toxic levels of the neurotoxic agent mercury could influence DNA by increasing L1 activities, specifically in neuronal cells, and may make these cells susceptible to neurodegeneration over time.

N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: Despite the burden of negative symptoms on quality of life in schizophrenic patients, no completely effective treatment has been developed to address such symptoms yet. Abnormalities in oxidative stress pathways have been recently demonstrated to be involved in the pathophysiology of schizophrenia, and a growing interest in antioxidant agents is emerging for targeting negative symptoms of schizophrenia. N-Acetylcysteine (NAC) is a potent antioxidant with neuroprotective properties. This study aimed to evaluate the possible effects of NAC as an adjunct to risperidone in treating negative symptoms of schizophrenia. MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study, 42 patients with chronic schizophrenia and a score of 20 or greater on the negative subscale of positive and negative syndrome scale (PANSS) were enrolled in the active phase of their illness. The participants were equally randomized to receive NAC (up to 2 g/d) or placebo, in addition to risperidone (up to 6 mg/d) for 8 weeks. The participants were rated using PANSS every 2 weeks, and the decrease of PANSS negative subscale score was considered as our primary outcome. RESULTS: By the study end point, NAC-treated patients showed significantly greater improvement in the PANSS total (P = 0.006) and negative subscale (P < 0.001) scores than that in the placebo group, but this difference was not significant for positive and general psychopathology subscales. There was no significant difference between the 2 groups in the frequency of adverse effects. CONCLUSIONS: NAC add-on therapy showed to be a safe and effective augmentative strategy for alleviating negative symptoms of schizophrenia.

Regulatory T cells in chronic lymphocytic leukemia: implication for immunotherapeutic interventions.

Identification of regulatory T cells (Tregs) has led to breaking the dichotomy of the Th1/Th2 axis in the immunopathology of several diseases such as autoimmune diseases and cancer. Despite the presence of extensive information about immunobiology of Tregs in pathogenesis of autoimmune diseases, little is known about the frequency and function of these cells in hematologic malignancies, particularly chronic lymphocytic leukemia (CLL). Recent data have demonstrated increased frequency and intact functional capacity of CD4(+) Tregs in CLL patients. However, the precise role of these cells in the immunopathology of CLL is not well known. While targeting Tregs in cancer diseases seems to be an interesting immunotherapeutic approach, such therapeutic interventions in CLL might be deleterious due to suppression of the tumor-specific adaptive and innate immune responses. Thus, the precise biological and regulatory functions of all Tregs subsets should be carefully investigated before planning any immunotherapeutic interventions based on targeting of Tregs. In this communication, we review the recent data published on immunobiology of Tregs in CLL and discuss about the possibility of targeting Tregs in CLL.

Does pioglitazone improve depression through insulin-sensitization? Results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression.

Thiazolidinediones have shown beneficial effects in short-term treatment of depression. However, it is unclear whether the antidepressant efficacy of these agents is related to their insulin-sensitizing action. We conducted the present study to compare the antidepressant efficacy of pioglitazone with another insulin-sensitizer, metformin, in obese patients with concomitant polycystic ovarian syndrome (PCOS) and major depressive disorder (MDD). In a six-week double-blind study, 50 patients with PCOS and MDD (DSM-IV-TR criteria) with Hamilton depression rating scale (HDRS) score of <20, randomly received pioglitazone (15 mg twice daily; PO) or metformin (750 mg twice daily; PO). Assessment was done using HDRS (weeks 0, 3, 6) together with fasting Insulin, glucose, and lipid profile, liver enzymes, homeostatic model assessment of insulin resistance (HOMA-IR), anthropometric measures, and serum androgens (weeks 0 and 6). Pioglitazone was superior to metformin in reducing HDRS scores at the end of the study [38.3% versus 8.3% reduction from baseline scores, F(1, 37) = 73.513, P<0.001]. Changes from baseline in HOMA-IR values at week 6 were not significantly different between the two groups (P = 0.888). Baseline (but not follow-up) HDRS and HOMA-IR values were significantly correlated (r = 0.393, P = 0.012). In multiple regression analysis, treatment with pioglitazone independent of HOMA-IR values predicted greater score reduction on HDRS at week 6 (standardized beta = 0.801, P<0.001). Biochemical and hormonal profile did not differ between the two groups at week 6. Metformin was associated with higher frequency of gastrointestinal side effects (P = 0.014). In summary, we showed that pioglitazone improved depression with mechanisms largely unrelated to its insulin-sensitizing action (registration number: IRCT201106081556N23).

Upregulation of CD200 is associated with Foxp3+ regulatory T cell expansion and disease progression in acute myeloid leukemia.

Immunosuppression in acute myeloid leukemia (AML) is an important mechanism of tumor escape. CD200, as an immunosuppressive molecule, is overexpressed in some hematological malignancies and it has also been shown to be an independent prognostic factor in AML. In the current study, simultaneous CD200 expression and Foxp3(+) regulatory T cell levels were investigated in Iranian patients with AML by flow cytometry. We also assessed the effect of CD200-CD200R blockade on Th1 and T-reg cytokine production and T cell proliferation in autologous AML- and monocyte-DC mixed lymphocyte reactions (MLRs). ELISA assay was performed to detect IL-2, IL-12, IFN-γ, IL-10, and TGF-ß production in MLR supernatants. Expression of Foxp3, IL-10, and TGF-ß mRNAs in MLRs were detected by real-time PCR. Our results demonstrated significant overexpression of CD200 (P = 0.001) in association with higher frequencies of Foxp3(+) T cells in AML patients (r = 0.8, P < 0.001). Blocking of CD200-CD200R interaction demonstrated a significant decrease in TGF-ß and IL-10 expression in AML-DC MLRs and a significant increase in IL-12 and IFN-γ expression in monocyte-DC MLRs. Elevated T cell levels with lower Foxp3 intensity was also shown in CD200-CD200R-blocked MLRs. Expression of IL-10 mRNA declined significantly only in AML-DC MLRs where CD200-CD200R interaction was blocked and the same result was observed for TGF-ß and Foxp3 mRNA in both AML- and monocyte-DC MLRs. These data present a significant role for CD200 in suppressing anti-tumor immune response through stimulation of regulatory mechanisms in AML patients and suggest that CD200 may have a prognostic value in this malignancy and its blockade may be used as a target for AML immunotherapy.

Bupropion versus methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder: randomized double-blind study.

OBJECTIVE: To compare the safety and efficacy of bupropion with methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: In a 6-week randomized double-blind study, 44 patients with a DSM-IV-TR diagnosis of ADHD were randomly assigned to receive bupropion 100-150 mg/day (100 mg/day for <30 kg and 150 mg/day for >30 kg) or methylphenidate 20-30 mg/day. Symptoms were assessed using Teacher and Parent Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) at baseline and weeks 3 and 6. RESULTS: Forty patients had at least one post-baseline measurement, and 38 patients completed the trial. No significant difference was found between the two groups on the Parent and Teacher ADHD-RS-IV scores ([F(1, 38) = 0.266, p = 0.609] and [F(1, 38) = 0.001, p = 0.972], respectively). By week 6, 18 patients (90%) in each group achieved response on the Parent scale (Fisher's exact test p-value = 1.0). With the Teacher ADHD-RS-IV used, eight (40%) patients in the bupropion group and 12 (60%) patients in the methylphenidate group achieved response by week 6 (χ(2) (1) = 1.600, p = 0.206). Headache was observed more frequently in the methylphenidate group. Frequency of other side effects was not significantly different between the two groups. CONCLUSIONS: Bupropion has a comparable safety and efficacy profile with methylphenidate in children and adolescents with ADHD.

Differential WNT gene expression in various subtypes of acute lymphoblastic leukemia.

BACKGROUND: Dysregulation of WNT signaling has been reported in many malignancies. OBJECTIVE: This study was conducted to investigate the expression pattern of 14 members of the WNT gene family in different immunophenotypic subtypes of ALL. METHODS: Semi-quantitative RT-PCR was performed on samples from 71 ALL patients and 36 age-matched healthy individuals. The ALL patients were categorized into B-ALL (76%), T-ALL (22.6%) and mixed lineage (1.4%) and the B-ALL cases were further classified into pro-B, pre-BI, pre-BII and immature/mature-B based on immuno-phenotypic results. RESULTS: Among the WNT genes, WNT-7B (p=0.026), WNT-9A (p=0.020) and WNT-16B (p=0.023) were significantly over-expressed, whereas WNT-2B (p=0.033), WNT-5A (p=0.016), WNT-7A (p<0.0001) and WNT-10A (p<0.0001) were down-regulated in B-ALL. Among the T-ALL subtype, however, significant down-regulation of WNT-2B, WNT-5B, WNT-7A, WNT-10A and WNT-11 was evident. Comparison between B-ALL subtypes showed significant over-expression of WNT-7B, WNT-9A and WNT-5B in certain subtypes. CONCLUSION: Our results suggest contribution of the WNT genes in leukemogenesis of ALL.

Gene amplification and overexpression of Aurora-C in breast and prostate cancer cell lines.

Human aurora kinases are three highly conserved serine/threonine kinases with regulatory function in chromosome alignment, chromosome segregation, and cytokinesis during cell cycle progression and their overexpression associates with malignant transformation and proliferation of cancer cells. Aurora genes are located at loci that are commonly altered in cancers. Aurora-A has oncogenic activity while Aurora-B does not. Aurora-C is only detected in mammals with involvement in meiosis. Oncogenic activity of Aurora-C is still in dispute. We evaluated the expression of three Aurora kinases by real-time RT-PCR in well-known breast and prostate cancer cell lines. Cell cycle was studied with flow cytometry. In both more invasive cell lines' p53-null cells, PC-3 and MDA-MB-231, an increase in mRNA expression of three Aurora kinases, especially Aurora-C, was observed. Genomic DNA was examined for gene amplification and aneuploidy as a mechanism of overexpression. At DNA level, only Aurora-C showed gene amplification in breast cancer cell lines (p < 0.005). Here we provide evidence for the first time of Aurora-C overexpression and gene amplification.

Correlation of adenosinergic activity with superior efficacy of clozapine for treatment of chronic schizophrenia: a double blind randomised trial.

OBJECTIVE: It has been proposed that a deficit of adenosinergic activity could contribute to the pathophysiology of schizophrenia. The authors undertook this study to further evaluate the level of adenosine deaminase (ADA) in patients with chronic schizophrenia treated with monotherapy of haloperidol, risperidone or clozapine and correlation between the ADA level with response to treatment. METHODS: The trial was a prospective, 8-week, double blind study of parallel groups of patients with chronic schizophrenia. Eligible participants in the study were 51 patients with chronic schizophrenia with ages ranging from 20 to 45 years. All participants were inpatients, in the active phase of illness, and met DSM-IV-TR criteria for schizophrenia. Patients were randomly allocated (17 patients in each group) to risperidone (6 mg/day) or haloperidol 15 mg/day or clozapine (300 mg/day). Serum ADA activity was measured at baseline and week 8. RESULTS: The plasma levels of ADA in patients with chronic schizophrenia who received clozapine were significantly higher than patients who received haloperidol. In addition, response to treatment was positively correlated with plasma levels of ADA only in the clozapine group (r = 0.46 and p = 0.04). CONCLUSION: The results indicate an increased activity of the enzyme ADA in the serum of schizophrenic patients being treated with clozapine and this increase may be correlated with clozapine's superior antipsychotic efficacy.