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Objectives Cytochrome P450 (CYP450) is a major enzyme system involved in drug metabolism as well as regulation of brain function. Although individual variability in CYP enzymes have been studied in terms of personality traits and treatment effects, no study up to now evaluated CYP polymorphisms in children with attention deficit/hyperactivity disorder (ADHD). We aimed to define the genetic profiles of CYP2D6 and CYP2C19 relevant alleles in children with ADHD according to treatment status and compare the frequencies according to past results. Methods Three hundred and seventeen patients with ADHD-Combined Presentation were enrolled; symptom severity was evaluated by parents and clinicians while adverse effects of previous treatments were evaluated with parent and child reports. Reverse blotting on strip assays was used for genotyping and descriptive and bivariate analyses were conducted. A p-value was set at 0.05 (two-tailed). Results Children were divided into treatment-naïve (n=194, 61.2%) and treatment-resistant (n=123, 38.8%) groups. Within the whole sample PM, EM and UM status according to 2D6 were 3.8% (n=12), 94.3% (n=299) and 21.9% (n=6); respectively. PM, IM, EM and UM status according to 2C19 were 2.5% (n=8), 19.8% (n=63), 48.6% (n=154) and 29.0% (n=92), respectively. No relationship with treatment resistance, comorbidity or gender could be found. Importantly, CYP2C19 UMs were significantly more frequent in ADHD patients compared to previous studies in the general population. Conclusions CYPs may be a rewarding avenue of research to elucidate the etiology and treatment of patients with ADHD.

Topal, Zehra/0000-0001-8397-5636; Kandemir, Hasan/0000-0002-1138-4973; Tufan, Evren/0000-0001-5207-6240; KUTUK, OZGUR/0000-0001-9854-7220 WOS: 000554002300029 PubMed: 32563959 Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in communication and social interaction as well as restricted interests and repetitive behaviors. The pathogenesis of ASD is not completely understood, but a growing body of research has demonstrated that the immune response may be a contributing factor in the etiology and/or ontogeny of ASD. The aim of this study was to determine the expression levels of IL-1 beta, IL-1 alpha, IL-4, IL-6, IL-17, TNF-alpha and TGF-beta in peripheral blood mononuclear cells of children with ASD and healthy controls in order to determine the contributions of cytokines to ASD. Within the study timeframe, 195 children with ASDs (80.5% male) and 162 controls (73.6% male) were enrolled. Most children with ASD had a comorbid disorder (n = 114, 58.5%), with the most common diagnoses as Intellectual Developmental Disorder (IDD, n = 64, 32.8%) and ADHD (n = 64, 32.8%). The majority of children with ASD had severe autistic symptoms as evaluated via Childhood Autism Rating Scale (CARS, n = 130, 64.6%). The mean CARS score in the ASD sample was 40.8 (S.D. = 7.6). The patients with ASD were found to have significantly higher levels of IL-6 (p < 0.001) and significantly lower levels of IL-17 (p < 0.05, all Bonferroni corrected). Treatment tended to affect IL-4 levels. Lastly, discriminant function analysis (DFA) revealed that a combination of IL-6, IL-17 and IL-1 alpha correctly classified 56.6% of cases. Despite extensive immunological evidence suggesting immune system aberrations, further research is required to clarify the relationship between immune profiles and ASD symptoms. Science Academy BAGEP program Ozgur Kutuk acknowledges support from Science Academy BAGEP program.

KUTUK, OZGUR/0000-0001-9854-7220; OZTOP, SIDIKA/0000-0001-5653-6080 WOS: 000567421400001 PubMed: 32901335 Ovarian cancer remains one of the most frequent causes of cancer-related death in women. Many patients with ovarian cancer suffer from de novo or acquired resistance to chemotherapy. Here, we report that RAB25 suppresses chemotherapy-induced mitochondrial apoptosis signaling in ovarian cancer cell lines and primary ovarian cancer cells. RAB25 blocks chemotherapy-induced apoptosis upstream of mitochondrial outer membrane permeabilization by either increasing antiapoptotic BCL-2 proteins or decreasing proapoptotic BCL-2 proteins. In particular, BAX expression negatively correlates with RAB25 expression in ovarian cancer cells. BH3 profiling assays corroborated that RAB25 decreases mitochondrial cell death priming. Suppressing RAB25 by means of RNAi or RFP14 inhibitory hydrocarbon-stapled peptide sensitizes ovarian cancer cells to chemotherapy as well as RAB25-mediated proliferation, invasion and migration. Our data suggest that RAB25 is a potential therapeutic target for ovarian cancer. TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [113S871]; Baskent University Research FundsBaskent University; Science Academy BAGEP program This study was supported by TUBITAK 113S871 and Baskent University Research Funds. Ozgur Kutuk acknowledges support from the Science Academy BAGEP program.

Antiapoptotic and proapoptotic BCL-2 protein family members regulate mitochondrial apoptotic pathway. Small molecule inhibitors of antiapoptotic BCL-2 proteins including BCL-2-specific inhibitor ABT-199 (Venetoclax) are in clinical development. However, the efficiency of ABT-199 as a single agent in solid tumors is limited. We performed a high-throughput RNAi kinome screen targeting 691 kinases to identify potentially targetable kinases to enhance ABT-199 response in breast cancer cells. Our studies identified Wee1 as the primary target kinase to overcome resistance to ABT-199. Depletion of Wee1 by siRNA-mediated knockdown or inhibition of Wee1 by the small molecule Wee1 inhibitor AZD1775 sensitized SKBR3, MDA-MB-468, T47D and CAMA-1 breast cancer cells to ABT-199 along with decreased MCL1. BH3-only proteins PUMA and BIM functionally contribute to apoptosis signaling following co-targeting BCL-2 and Wee1. Suppression of Wee1 function increased mitochondrial cell death priming. Furthermore, we found that Wee1 inhibition altered MCL1 phosphorylation and protein stability, which led to HUWE1-mediated MCL1 degradation. Our findings suggest that Wee1 inhibition can overcome resistance to ABT-199 and provide a rationale for further translational investigation of BCL-2 inhibitor/Wee1 inhibitor combination in breast cancer.

In this work we described the synthesis and evaluation of cytotoxic and apoptotic activity of novel pyrrolopyrimidine derivatives against A549, PC3 and MCF-7 cells. Among the synthesized compounds, 6b, 8a, 9a and 7a, 8b displayed the significant cytotoxic activities against A549 and PC3 cells with IC50 value of 0.35, 1.48, 1.56 and 1.04, 1.89 µM, respectively. It was found that A549 cells were more sensitive to synthesized compounds than PC3 and MCF-7 cells. In order to evaluate the mechanism of cytotoxic activity in A549, compounds 6b, 8a and 9a were selected for further studies. Annexin V binding assay and western blot analysis results revealed that 6b, 8a and 9a induced apoptosis in A549 cells by intrinsic apoptotic pathway through the activation pro-apoptotic proteins such as Bim, Bax, Bak, Puma and deactivation of anti-apoptotic proteins including Bcl-2, Mcl-1 and Bcl-XL accompanied by the activation of caspase-3, caspase-9 and cleavage of PARP. Also, compounds 6b, 8a and 9a triggered apoptosis in HCT116 wt cells via activation of caspase-3 and caspase-9, but not in HCT116 Bax/Bak KO cells, indicating resistance to 6b, 8a and 9a treatment.

A series of novel pyrrolopyrimidine urea derivatives were synthesized and evaluated for their anticancer activity against colon cancer cell lines. Compounds showed the remarkable cytotoxic activity on HCT-116 wt cell line. The most potent compound 4c (IC50 = 0.14 μM) induced apoptosis in HCT-116 wt and HCT-116 p53-/- cell lines. Otherwise, treatment of HCT-116 BAX-/-BAK-/- cells with compound 4c didn't lead to activation of apoptosis, suggesting that compound 4c induces apoptotic cell death by activating BAX/BAK-dependent pathway. Moreover, while the compound 4c increase the activation of caspase-3 and caspase-9 levels in HCT-116 wt and HCT-116 p53-/- cells, caspase-3 or caspase-9 activation was not observed in HCT-116 BAX-/-BAK-/- cells. In addition, compound 4c induced mitochondrial apoptosis in cells grown as oncospheroids, which better mimic the in vivo milieu of tumors. 4c treatment also activated JNK along with inhibition of prosurvival kinases such as Akt and ERK 1/2 in HCT-116 wt and HCT-116 p53 -/- cells as well as in HCT-116 BAX-/-BAK-/- cells. Notably, our results indicated that compound 4c induced mitochondrial apoptosis through activation p53-independent apoptotic signaling pathways.

PubMedID: 17885857 Little is known about the contribution of indoor molds to the symptoms of asthma and/or rhinitis in children monosensitized to molds. We aimed to investigate the effect of indoor mold spore concentrations on daily symptoms of asthma and/or rhinitis in children monosensitized to molds. Nineteen children with asthma and/or rhinitis sensitized only to molds recorded their daily symptoms and peak expiratory flow (PEF) values to the diaries, from February 2005 to January 2006. In this study period, indoor mold concentrations were measured monthly from the living rooms/bedrooms. The median indoor mold concentration was 37.5 CFU/m3. Most commonly recovered indoor molds were Cladosporium (26.4%), Penicillium (24.7%), and Aspergillus (7%). Significant correlation was not found between indoor mold concentrations and daily rhinitis score (r = -0.021, p = 0.932), daily asthma score (r = 0.155, p = 0.554), daily morning PEF (r = -0.056, p = 0.475), and evening PEF (r = -0.057, p = 0.471). The effect of indoor molds is not evident on the symptoms of our patients with asthma and/or rhinitis monosensitized to molds. Copyright © 2007 Informa Healthcare USA, Inc.

TEZ6150 Tez (Yüksek Lisans) -- Çukurova Üniversitesi, Adana, 2006. Kaynakça (s.67-76) var. viii, 77 s. : rnk. ; 29 cm. In this study, It was tried to determine the isolation, identification, seasonal distribution and correlation of allergic disases of outdoor fungi in ADANA, at 6 different area. For isolation of atmospheric fungi, samples collected from air with ECO MASS 100 Aerosampler equipment and plated on to the Rose Bengal Streptomycine Agar, then all plates incubated at 25.C for 14 days. Genus of the isolated fungus were identified based on micro- and macromorphology with the pigmentation of colonies at the bottom and surface of grown on CZ, MEA ad PDA media. Sampling was performed once a month, twelve times during the year, from february 2005 to January 2006. Total 3220 fungi colonies were isolated and as a result total 9 different genus of fungi were identified. These are Cladosporium 1436 (44,5%), Penicillium 644 (20%), Aspergillus 548 (17.0%), Alternaria 176 (5.4%), steril 63 (1.95%), Rhizopus 44 (1.36%), Fusarium 29 (0.90%), Acremonium18 (0.55%) Trichoderma 9 (0.27%), Chatemonium 1 (0.03%) and the others 252 (%7.8). A significant correlation was found between atmospheric fungi concentration and allergic diseases, the pediatric allergy clinic of Çukurova University Hospital, Bu çalışmada, Adana ilindeki 6 farklı istasyondan ev dışı (outdoor) mantarların izolasyonu, identifikasyonu, mevsimsel dağılımı ve alerjik hastalıklarla ilişkisi saptanmaya çalışılmıştır. Atmosferik Fungusların izolasyonu amacıyla örnekler, ECO MASS 100 Mikrobiyal Hava İzleme Sistemi kullanılarak Rose Bengal Streptomycine Agarlı Besiyerlerine ekim yapılmıştır. PDA, MEA, CZ besiyerlerindeki üreme davranışları, koloni morfolojisi, pigment oluşumu, petri kutusunda alt ve üstten görünüşleri, spor ve hifsel yapılarının mikroskobik incelenmesi gibi parametrelere göre tanımlama kriterleri dikkate alınarak identifikasyonları genus düzeyinde gerçekleştirilmiştir. Örnekleme Şubat 2005-Ocak 2006 tarihleri arasında ayda bir kez olmak koşuluyla 12 kez yapılmıştır. Toplam 3220 mantar kolonisi izole edilmiştir. İzole edilen kolonilerin tanımlanması sonucu 9 farklı mantar cinsi saptanmıştır. Bunlar; Cladosporium 1436 (%44,5), Penicillium 644 (%20), Aspergillus 548 (%17.0), Alternaria 176 (%5.4), steril 63 (%1.95), Rhizopus 44 (%1.36), Fusarium 29 (%0.90), Acremonium18 (%0.55) Trichoderma 9 (%0.27, Chatemonium 1 (%0.03) ve diğerleridir 252 (%7.8) Atmosferdeki mantar konsantrasyonu ile alerjik çocukların astım skorları ve rinit skorları arasında ileri düzeyde anlamlı ilişki saptanmıştır. Bu çalışma Ç.Ü. Bilimsel Araştırma Projeleri Birimi Tarafından Desteklenmiştir. Proje No:FEF2005YL2