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Publication Open Access A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability(eLife Sciences Publications, 2018) Chia, Poh Hui; Zhong, Franklin Lei; Niwa, Shinsuke; Bonnard, Carine; Utami, Kagistia Hana; Zhang, Ruizhu; Lee, Hane; Eskin, Ascia; Nelson, Stanley F.; Xie, William H.; Al-Tawalbeh, Samah; El-Khateeb, Mohammad; Shboul, Mohammad; Pouladi, Mahmoud A.; Al-Raqad, Mohammad; N/A; Reversade, Bruno; Faculty Member; School of MedicineCalcium/calmodulin-dependent protein kinase II (CAMK2) plays fundamental roles in synaptic plasticity that underlies learning and memory. Here, we describe a new recessive neurodevelopmental syndrome with global developmental delay, seizures and intellectual disability. Using linkage analysis and exome sequencing, we found that this disease maps to chromosome 5q31.1-q34 and is caused by a biallelic germline mutation in CAMK2A. The missense mutation, p. His477Tyr is located in the CAMK2A association domain that is critical for its function and localization. Biochemically, the p.His477Tyr mutant is defective in self-oligomerization and unable to assemble into the multimeric holoenzyme.ln vivo, CAMK2A(H477Y) failed to rescue neuronal defects in C. elegans lacking unc-43, the ortholog of human CAMK2A. In vitro, neurons derived from patient iPSCs displayed profound synaptic defects. Together, our data demonstrate that a recessive germline mutation in CAMK2A leads to neurodevelopmental defects in humans and suggest that dysfunctional CAMK2 paralogs may contribute to other neurological disorders.
Publication Metadata only A novel flexible progestin primed ovarian stimulatıon protocol: Comparıson of pregnancy outcomes with the flexible GnRH antagonist protocol in an oocyte donation program(Oxford Univ Press, 2019) Angun, B.; N/A; Yıldız, Şule; Türkgeldi, Engin; Ata, Mustafa Barış; Faculty Member; Faculty Member; Faculty Member; School of Medicine; Koç University Hospital; 134205; 329649; 182910N/APublication Metadata only A survey of women who cryopreserved oocytes for non-medical indications(Elsevier Science Inc, 2017) N/A; N/A; N/A; N/A; Ata, Ayşe Seyhan; Akın, Öznur Dündar; Urman, Cumhur Bülent; Yakın, Kayhan; Doctor; Doctor; Faculty Member; Faculty Member; N/A; N/A; School of Medicine; School of Medicine; American Hospital; N/A; N/A; 12147; 106822Objective: What are the expectations, experiences, and fertility awareness status of women who underwent social oocyte cryopreservation? Design: All women who underwent social oocyte cryopreservation between January 2015 and June 2016 were recruited. One hundred thirty three women were invited to participate in a survey at least 6 months after completion of the treatment cycle. Materials and Methods: Eigthy-one patients completed the survey.All women were given personalized counselling before starting the treatment cycle. Counselling included, chances of natural conception at a given age and the concept of ovarian reserve. The questionnaire investigated initial motivation towards freezing, intentions to use cryopreserved oocytes, treatment experience, awareness of fertility and knowledge about chances of having a live birth with their frozen oocytes. Results: The mean (± standard deviation) age at the time of oocyte freezing was 38.5 ± 2.68 years. The average number (min - max) of mature oocytes cryopreserved was 5.48 ± 6.6 (1-16). Two major motivations were absence of a male partner at the time of decision (40%) and an anticipated age-related fertility decline (42%). Majority of women (42%) opted to limit the use of cryopreserved oocytes up to the age of 45, and 51% of bankers wished that they had completed their family by the age of 35. 41% of the women told that they would donate their oocytes for research, 35% discard, and 24% donate to other infertile couples, if they did not use for own reproduction. 54% of patients thought that they did not have an adequate number of stored oocytes, 43 % wanted to do another cycle. 59% of the latter, were not able to undergo another cycle since they couldn’t afford another cycle. 42% and 35% of the women reported anxiety and injections, respectively, as the most challenging factor during treatment. Almost 60% overestimated the chances of natural conception, as well as the success of IVF at the age of 40 years. Half of the oocyte bankers reported that fertility declined between ages 35-39 but only 28% of patients estimated the live birth rate per cryopreserved oocyte correctly. Overall 98.8% stated that they would recommend oocyte cryopresevation to a friend and 72% felt more secure in terms of reproductive potential. Conclusions: Despite comprehensive personalized counselling prior to the start of ovarian stimulation, many women, as well as some health care policy makers do not seem to have a realistic understanding of reproductive ageing. Overestimaing effectiveness of assisted reproductive technology and arbitrarily delaying childbearing can lead to future childlessnes. Even though gamete cryopreservation provides some insurance, overestimating the effectiveness of oocyte cryopreservation can also lead to a false sense of security. Increasing awareness and knowledge about reproductive ageing is needed.Publication Metadata only A survey of women who cryopreserved oocytes for non-medical indications (social fertility preservation)(Springer, 2021) Akin, Öznur Dündar; Ertaş, Sinem; N/A; N/A; N/A; N/A; Ata, Ayşe Seyhan; Ata, Mustafa Barış; Yakın, Kayhan; Urman, Cumhur Bülent; Doctor; Faculty Member; Faculty Member; Faculty Member; N/A; School of Medicine; School of Medicine; School of Medicine; American Hospital; School of Medicine; N/A; N/A; N/A; 182910; 106822; 12147To evaluate the expectations, experiences, and fertility awareness status of women who underwent social oocyte cryopreservation. Cohort survey study was conducted at an academic medical center. All women who underwent social oocyte cryopreservation between January 2015 and June 2016 were recruited. One hundred thirty-three women were contacted by phone to participate in a survey. The questionnaire investigated the initial motivation towards freezing, intentions to use cryopreserved oocytes, treatment experience, awareness of fertility and knowledge about chances of having a live birth with their frozen oocytes. The mean age at the time of oocyte freezing was 38.5 +/- 2.68 years. The average number of mature oocytes cryopreserved was 5.48 +/- 6.6 (1-16). Two major motivations were absence of a male partner (40%) and an anticipated age-related fertility decline (42%). Almost 60% overestimated the chances of natural conception, as well as the success of IVF at the age of 40 years. Half of the oocyte bankers reported that fertility declined between ages 35 and 39, but only 28% of patients estimated the live birth rate per cryopreserved oocyte correctly. Overall 98.8% stated that they would recommend oocyte cryopresevation to a friend, and 72% felt more secure in terms of reproductive potential. Despite comprehensive personalized counseling prior to the start of ovarian stimulation, many women do not seem to have a realistic understanding of reproductive aging. Even though gamete cryopreservation provides some insurance, overestimating the effectiveness of oocyte cryopreservation can also lead to a false sense of security.Publication Metadata only Adaptive tracking algorithm for trajectory analysis of cells and layer-by-layer assessment of motility dynamics(Pergamon-Elsevier Science Ltd, 2022) Bayraktar, Halil; N/A; Department of Molecular Biology and Genetics; Qureshi, Mohammad Haroon; PhD Student; Faculty Member; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; Graduate School of Sciences and Engineering; College of Sciences; N/A; 105301Tracking biological objects such as cells or subcellular components imaged with time-lapse microscopy enables us to understand the molecular principles about the dynamics of cell behaviors. However, automatic object detection, segmentation and extracting trajectories remain as a rate-limiting step due to intrinsic challenges of video processing. This paper presents an adaptive tracking algorithm (Adtari) that automatically finds the op-timum search radius and cell linkages to determine trajectories in consecutive frames. A critical assumption in most tracking studies is that displacement remains unchanged throughout the movie and cells in a few frames are usually analyzed to determine its magnitude. Tracking errors and inaccurate association of cells may occur if the user does not correctly evaluate the value or prior knowledge is not present on cell movement. The key novelty of our method is that minimum intercellular distance and maximum displacement of cells between frames are dynamically computed and used to determine the threshold distance. Since the space between cells is highly variable in a given frame, our software recursively alters the magnitude to determine all plausible matches in the trajectory analysis. Our method therefore eliminates a major preprocessing step where a constant distance was used to determine the neighbor cells in tracking methods. Cells having multiple overlaps and splitting events were further evaluated by using the shape attributes including perimeter, area, ellipticity and distance. The features were applied to determine the closest matches by minimizing the difference in their magnitudes. Finally, reporting section of our software were used to generate instant maps by overlaying cell features and trajectories. Adtari was validated by using videos with variable signal-to-noise, contrast ratio and cell density. We compared the adaptive tracking with constant distance and other methods to evaluate performance and its efficiency. Our algorithm yields reduced mismatch ratio, increased ratio of whole cell track, higher frame tracking efficiency and allows layer-by-layer assessment of motility to characterize single-cells. Adaptive tracking provides a reliable, accurate, time efficient and user-friendly open source software that is well suited for analysis of 2D fluorescence microscopy video datasets.Publication Metadata only Anomalies in the transcriptional regulatory network of the Yeast Saccharomyces cerevisiae(Elsevier, 2010) N/A; Department of Physics; Tuğrul, Murat; Kabakçıoğlu, Alkan; N/A; Faculty Member; Department of Physics; Graduate School of Sciences and Engineering; College of Sciences; N/A; 49854We investigate the structural and dynamical properties of the transcriptional regulatory network of the Yeast Saccharomyces cerevisiae and compare it with two "unbiased" ensembles: one obtained by reshuffling the edges and the other generated by mimicking the transcriptional regulation mechanism within the cell. Both ensembles reproduce the degree distributions (the first-by construction-exactly and the second approximately), degree-degree correlations and the k-core structure observed in Yeast. An exceptionally large dynamically relevant core network found in Yeast in comparison with the second ensemble points to a strong bias towards a collective organization which is achieved by subtle modifications in the network's degree distributions. We use a Boolean model of regulatory dynamics with various classes of update functions to represent in vivo regulatory interactions. We find that the Yeast's core network has a qualitatively different behavior, accommodating on average multiple attractors unlike typical members of both reference ensembles which converge to a single dominant attractor. Finally, we investigate the robustness of the networks and find that the stability depends strongly on the used function class. The robustness measure is squeezed into a narrower band around the order-chaos boundary when Boolean inputs are required to be nonredundant on each node. However, the difference between the reference models and the Yeast's core is marginal, suggesting that the dynamically stable network elements are located mostly on the peripherals of the regulatory network. Consistently, the statistically significant three-node motifs in the dynamical core of Yeast turn out to be different from and less stable than those found in the full transcriptional regulatory network.Publication Metadata only Are live birth rate and obstetric outcomes different between immediate and delayed embryo transfers following a freeze-all cycle? a retrospective study combined with a meta-analysis(Oxford Univ Press, 2021) N/A; N/A; N/A; N/A; N/A; N/A; Yıldız, Şule; Türkgeldi, Engin; Kalafat, Erkan; Gökyer, Dilan; Keleş, İpek; Ata, Mustafa Barış; Faculty Member; Faculty Member; Faculty Member; Undergraduate Student; Doctor; Faculty Member; School of Medicine; School of Medicine; School of Medicine; School of Medicine; N/A; School of Medicine; Koç University Hospital; 134205; 329649; 197389; N/A; N/A; 182910Study Question: Do livebirth rate (LBR), obstetric and perinatal outcomes vary between frozen embryo transfers (FET) in the first or subsequent menstrual cycles following a freeze-all approach? Summary Answer: Immediate FET has a higher LBR and similar perinatal outcomes than delayed FET. Quantitative synthesis of available literature shows an increased LBR with immediate transfer. What is Known Already: Whether FET should be done in the first menstrual cycle following oocyte collection (OC) is controversial and the duration of a possible detrimental effect of supraphysiological sex steroid levels on pregnancy outcome is unknown. A multinational survey centers showed that, 61% of clinicians prefer to wait for a washout period before proceeding to FET, even after a failed fresh embryo transfer. Limited number of studies compared FET in the first menstrual cycle with delayed FET in a subsequent cycle with varying results. There is limited data on obstetric outcomes of pregnancies resulting from FET in the first menstrual cycle. Study Design, Size, Duration: 198 women who underwent a freeze-all cycle followed by FET between July 2017 and June 2020 were included. 119 FET in the first menstrual cycle (<30 days from oocyte collection) and 79 FET in subsequent cycles (>30 days from oocyte collection) were retrospectively compared. MEDLINE was searched on 01 January 2021 using relevant keywords. Cohort studies comparing immediate versus delayed transfer following freeze all cycles were included and quantitative summary for LBR was obtained. Participants/Materials, Setting, Methods: Freeze-all was undertaken when (i) the woman is deemed to be at high risk for OHSS, (ii)serum progesterone level is > 1.5 ng/ml on the day of trigger, (iii)preimplantation genetic testing is planned, (iv)the woman will undergo surgery prior to ET, (v)couple preference. Main Results and the Role of Chance: Baseline characteristics were similar between the groups except for antral follicle count (22 vs 18, MD = 5, 95% CI = 0 to 8), and number of metaphase-two oocytes (13 vs 10, MD = 3, 95% CI = 1 to 6) all of which were significantly higher in the immediate transfer group. Clinical pregnancy rate (CPR) per ET was similar in two groups (50.4% vs 44.3%, RR = 1.14, 95% CI = 0.84 to 1.54). Miscarriage rate per pregnancy was significantly lower (12.3 vs 31.1, RR = 0.40, 95% CI = 0.19 to 0.84) and LBR per ET was significantly higher (42.9 vs 26.6, RR = 1.61, 95% CI = 1.06 to 2.46) in the immediate transfer group. Median gestational age at delivery was similar (267.5 (262.5–273) vs 268 (260–271.5) days, MD = 1.00, 95% CI= –4.00 to 5.00). Median birthweight was significantly higher in the delayed transfer group (3520 vs 3195 grams, MD= –300, 95% CI= –660 to –20 grams). Birthweight percentile, height at birth and head circumference were similar between groups. Literature search revealed 1712 studies from which nine were eligible for quantitative summary. Cumulative risk ratio showed a 10% increase in LBR with immediate transfer ompared to delayed transfer (RR = 1.10, 95% CI = 1.01 – 1.20, I2=67%, 17369 embryo transfers). Limitations, Reasons for Caution: Our study is limited by its retrospective design and relatively limited sample size for multivariate analyses. Yet, it is reassuring that the majority of our findings are consistent with previous publications. Wider Implications of the Findings: The hypotheses generated by our retrospective findings, i.e., FET in the immediate menstrual cycle resembling fresh ETs with strong trends towards lower birthweight and lower incidence of preeclampsia is noteworthy for the design of future studies, and these outcomes should be followed and reported.Publication Metadata only Assessment of the reliability of the Bologna criteria in predicting ovarian response and live birth rates in subsequent IVF attempts: An external validity study(Oxford University Press (OUP), 2017) Işıklar, A.; Balaban, B.; N/A; N/A; N/A; N/A; Yakın, Kayhan; Öktem, Özgür; Yıldız, Şule; Urman, Cumhur Bülent; Faculty Member; Faculty Member; Faculty Member; Faculty Member; School of Medicine; School of Medicine; School of Medicine; School of Medicine; 106822; 102627; 134205; 12147N/APublication Metadata only Coculture model of blood-brain barrier on electrospun nanofibers(TUBITAKScientific and Technical Research Council Turkey, 2020) Bayir, Ece; Dogan, Sule; Öztürk, Şükrü; Sendemir, Aylin; N/A; Özyurt, Mustafa Görkem; PhD Student; Graduate School of Sciences and Engineering; School of Medicine; N/AThe blood-brain barrier (BBB) is a control mechanism that limits the diffusion of many substances to the central nervous system (CNS). In this study, we designed an in-vitro 3-dimensional BBB system to obtain a fast and reliable model to mimic drug delivery characteristics of the CNS. A support membrane of polycaprolactone nanofiber surfaces was prepared using electrospinning. After confirming the fiber morphology and size, endothelial cells (HUVEC) and glial cells were cultured on either side of this membrane. The model's similarity to in vivo physiology was tested with a home-designed transmembrane resistance (TR) device, with positive and negative control molecules. Finally, 2 doses of methotrexate (MTX), a chemotherapy agent, were applied to the model, and its permeability through the model was determined indirectly by a vitality test on the MCF-7 cell line. Nicotine, the positive control, completed its penetration through the model almost instantly, while albumin, the negative control, was blocked significantly even after 2 days. MTX reached a deadly threshold 24 h after application. The TR value of the model was promising, being around 260 ohm.cm2. The provided model proposes a disposable and reliable tool for investigating drug permeability through the BBB and has the potential to reduce the number of animal experiments.Publication Metadata only Comparison of two intraoperative examination methods for the diagnosis of sentinel lymph node metastasis in clinically early stage endometrial cancer: a Turkish Gynecologic Oncology Group Study (TRSGO-SLN-003)(Elsevier, 2021) Taskin, Salih; Varli, Bulut; Altin, Duygu; Takmaz, Ozguc; Ersoz, Cevriye Cansiz; Turan, Hasan; Zeren, Handan; Havare, Semiha Battal; Karabuk, Emine; Naki, Murat; Gungor, Mete; Kose, Faruk; Ortac, Firat; Arvas, Macit; Ayhan, Ali; N/A; Vatansever, Doğan; Taşkıran, Çağatay; Bulutay, Pınar; Faculty Member; Faculty Member; Teaching Faculty; School of Medicine; School of Medicine; School of Medicine; 193687; 134190; 133565Objective: This study evaluated diagnostic accuracy of intraoperative sentinel lymph node (SLN) frozen section examination and scrape cytology as a possible solution for management of SLN positive patients. Study Design: Clinically early-stage endometrial cancer patients who underwent SLN algorithm and intraoperative SLN examination were analyzed. Findings were compared with final pathology results and diagnostic accuracy of frozen section and scrape cytology were evaluated. Results: Of the 208 eligible patients, 100 patients (48 %) had frozen section examination and 108 (52 %) had scrape cytology of the SLN. Intraoperative examination and final pathology were negative for metastasis in 187/208 (90 %) cases. The rest 21 cases had metastatic SLNs according to final pathology. 12 of 21 (57 %) metastases were classified as macrometastasis. Intraoperative examination of SLNs correctly identified 13 cases (true positive) and missed 8 cases (false negative). Five of 8 false negative cases had micrometastasis or isolated tumor cells. Considering identification of macrometastasis, sensitivity and negative predictive value were 85.71 % and 98.94 %, respectively, for the frozen section and 60.00 % and 98.15 %, respectively, for the scrape cytology. Conclusion: Frozen section examination of SLN has higher sensitivity in detecting macrometastasis compared to scrape cytology and it could help the surgeon in decision for further lymphadenectomy intraoperatively.