Kerem Nernekli

All Publications

• SenNet recommendations for detecting senescent cells in different tissues. Nature reviews. Molecular cell biology Suryadevara, V., Hudgins, A. D., Rajesh, A., Pappalardo, A., Karpova, A., Dey, A. K., Hertzel, A., Agudelo, A., Rocha, A., Soygur, B., Schilling, B., Carver, C. M., Aguayo-Mazzucato, C., Baker, D. J., Bernlohr, D. A., Jurk, D., Mangarova, D. B., Quardokus, E. M., Enninga, E. A., Schmidt, E. L., Chen, F., Duncan, F. E., Cambuli, F., Kaur, G., Kuchel, G. A., Lee, G., Daldrup-Link, H. E., Martini, H., Phatnani, H., Al-Naggar, I. M., Rahman, I., Nie, J., Passos, J. F., Silverstein, J. C., Campisi, J., Wang, J., Iwasaki, K., Barbosa, K., Metis, K., Nernekli, K., Niedernhofer, L. J., Ding, L., Wang, L., Adams, L. C., Ruiyang, L., Doolittle, M. L., Teneche, M. G., Schafer, M. J., Xu, M., Hajipour, M., Boroumand, M., Basisty, N., Sloan, N., Slavov, N., Kuksenko, O., Robson, P., Gomez, P. T., Vasilikos, P., Adams, P. D., Carapeto, P., Zhu, Q., Ramasamy, R., Perez-Lorenzo, R., Fan, R., Dong, R., Montgomery, R. R., Shaikh, S., Vickovic, S., Yin, S., Kang, S., Suvakov, S., Khosla, S., Garovic, V. D., Menon, V., Xu, Y., Song, Y., Suh, Y., Dou, Z., Neretti, N. 2024

  Abstract

  Once considered a tissue culture-specific phenomenon, cellular senescence has now been linked to various biological processes with both beneficial and detrimental roles in humans, rodents and other species. Much of our understanding of senescent cell biology still originates from tissue culture studies, where each cell in the culture is driven to an irreversible cell cycle arrest. By contrast, in tissues, these cells are relatively rare and difficult to characterize, and it is now established that fully differentiated, postmitotic cells can also acquire a senescence phenotype. The SenNet Biomarkers Working Group was formed to provide recommendations for the use of cellular senescence markers to identify and characterize senescent cells in tissues. Here, we provide recommendations for detecting senescent cells in different tissues based on a comprehensive analysis of existing literature reporting senescence markers in 14 tissues in mice and humans. We discuss some of the recent advances in detecting and characterizing cellular senescence, including molecular senescence signatures and morphological features, and the use of circulating markers. We aim for this work to be a valuable resource for both seasoned investigators in senescence-related studies and newcomers to the field.

  View details for DOI 10.1038/s41580-024-00738-8

  View details for PubMedID 38831121

  View details for PubMedCentralID 5643029

• Stereotactic radiosurgery for facial nerve hemangioma: Case report and systematic review. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Park, D. J., Hori, Y. S., Nernekli, K., Persad, A. R., Tayag, A., Ustrzynski, L., Emrich, S. C., Hancock, S. L., Chang, S. D. 2024; 126: 21-25

  Abstract

  Facial nerve hemangiomas (FNHs) are rare tumors that primarily occur near the geniculate ganglion in the temporal bone. Despite their rarity, they can cause significant facial nerve dysfunction. The optimal management approach for FNHs remains uncertain, with surgery being the mainstay but subject to debate regarding the extent of resection and preservation of the facial nerve.Systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We queried the PubMed/Medline (accessed on 5 March 2024) electronic database using combinations of the following search terms and words text: "geniculate ganglion hemangioma", "ganglional hemangioma", "hemangioma of the facial nerve", "facial hemangioma", and "intratemporal hemangioma".We identified a total of 30 literatures (321 patients). The most common site involved for the facial nerve hemangioma was the geniculate ganglion area followed by internal auditory canal, tympanic segment, labyrinthine segment and mastoid involvement. All patients were treated with conservative management or surgery. We report a 48-year-old female patient with HB grade 2 facial palsy and hemifacial spasm underwent SRS using Cyberknife technology. The treatment targeted the FNH in the left internal acoustic canal near the geniculate ganglion. Six months post-treatment, clinical improvement was evident, and lesion control was confirmed in a follow-up brain MRI.The rarity of FNHs contributes to the lack of consensus on optimal management. This illustrative case demonstrates the feasibility of SRS as a standalone treatment for FNHs.

  View details for DOI 10.1016/j.jocn.2024.05.023

  View details for PubMedID 38823231

• Automatic Segmentation of Vestibular Schwannomas: A Systematic Review. World neurosurgery Nernekli, K., Persad, A. R., Hori, Y. S., Yener, U., Celtikci, E., Sahin, M. C., Sozer, A., Sozer, B., Park, D. J., Chang, S. D. 2024

  Abstract

  Vestibular Schwannomas (VS) are benign tumors often monitored over time, with measurement techniques for assessing growth rates subject to significant interobserver variability. Automatic segmentation of these tumors could provide a more reliable and efficient for tracking their progression, especially given the irregular shape and growth patterns of VS.Various studies and segmentation techniques employing different Convolutional Neural Network architectures and models, such as U-Net and CATS, were analyzed. Models were evaluated based on their performance across diverse datasets, and challenges, including domain shift and data sharing, were scrutinized.Automatic segmentation methods offer a promising alternative to conventional measurement techniques, offering potential benefits in precision and efficiency. However, these methods are not without challenges, notably the "domain shift" that occurs when models trained on specific datasets underperform when applied to different datasets. Techniques such as domain adaptation, domain generalization, and data diversity were discussed as potential solutions.Accurate measurement of VS growth is a complex process, with volumetric analysis currently appearing more reliable than linear measurements. Automatic segmentation, despite its challenges, offers a promising avenue for future investigation. Robust, well-generalized models could potentially improve the efficiency of tracking tumor growth, thereby augmenting clinical decision-making. Further work needs to be done to develop more robust models, address the domain shift, and enable secure data sharing for wider applicability.

  View details for DOI 10.1016/j.wneu.2024.04.145

  View details for PubMedID 38685346

• Two-Photon Intravital Microscopy of Glioblastoma in a Murine Model. Journal of visualized experiments : JoVE Nernekli, K., Mangarova, D. B., Shi, Y., Varniab, Z. S., Chang, E., Tikenogullari, O. Z., Pisani, L., Tikhomirov, G., Wang, G., Daldrup-Link, H. E. 2024

  Abstract

  The delivery of intravenously administered cancer therapeutics to brain tumors is limited by the blood-brain barrier. A method to directly image the accumulation and distribution of macromolecules in brain tumors in vivo would greatly enhance our ability to understand and optimize drug delivery in preclinical models. This protocol describes a method for real-time in vivo tracking of intravenously administered fluorescent-labeled nanoparticles with two-photon intravital microscopy (2P-IVM) in a mouse model of glioblastoma (GBM). The protocol contains a multi-step description of the procedure, including anesthesia and analgesia of experimental animals, creating a cranial window, GBM cell implantation, placing a head bar, conducting 2P-IVM studies, and post-surgical care for long-term follow-up studies. We show representative 2P-IVM imaging sessions and image analysis, examine the advantages and disadvantages of this technology, and discuss potential applications. This method can be easily modified and adapted for different research questions in the field of in vivo preclinical brain imaging.

  View details for DOI 10.3791/66304

  View details for PubMedID 38497657

• Musculoskeletal imaging of senescence. Skeletal radiology Daldrup-Link, H. E., Suryadevara, V., Tanyildizi, Y., Nernekli, K., Tang, J. H., Meade, T. J. 2024

  Abstract

  Senescent cells play a vital role in the pathogenesis of musculoskeletal (MSK) diseases, such as chronic inflammatory joint disorders, rheumatoid arthritis (RA), and osteoarthritis (OA). Cellular senescence in articular joints represents a response of local cells to persistent stress that leads to cell-cycle arrest and enhanced production of inflammatory cytokines, which in turn perpetuates joint damage and leads to significant morbidities in afflicted patients. It has been recently discovered that clearance of senescent cells by novel "senolytic" therapies can attenuate the chronic inflammatory microenvironment of RA and OA, preventing further disease progression and supporting healing processes. To identify patients who might benefit from these new senolytic therapies and monitor therapy response, there is an unmet need to identify and map senescent cells in articular joints and related musculoskeletal tissues. To fill this gap, new imaging biomarkers are being developed to detect and characterize senescent cells in human joints and musculoskeletal tissues. This review article will provide an overview of these efforts. New imaging biomarkers for senescence cells are expected to significantly improve the specificity of state-of-the-art imaging technologies for diagnosing musculoskeletal disorders.

  View details for DOI 10.1007/s00256-024-04585-8

  View details for PubMedID 38329533

  View details for PubMedCentralID 5785239

• Beyond human in neurosurgical exams: ChatGPT's success in the Turkish neurosurgical society proficiency board exams. Computers in biology and medicine Sahin, M. C., Sozer, A., Kuzucu, P., Turkmen, T., Sahin, M. B., Sozer, E., Tufek, O. Y., Nernekli, K., Emmez, H., Celtikci, E. 2023; 169: 107807

  Abstract

  Chat Generative Pre-Trained Transformer (ChatGPT) is a sophisticated natural language model that employs advanced deep learning techniques and is trained on extensive datasets to produce responses akin to human conversation for user inputs. In this study, ChatGPT's success in the Turkish Neurosurgical Society Proficiency Board Exams (TNSPBE) is compared to the actual candidates who took the exam, along with identifying the types of questions it answered incorrectly, assessing the quality of its responses, and evaluating its performance based on the difficulty level of the questions. Scores of all 260 candidates were recalculated according to the exams they took and included questions in those exams for ranking purposes of this study. The average score of the candidates for a total of 523 questions is 62.02 ± 0.61 compared to ChatGPT, which was 78.77. We have concluded that in addition to ChatGPT's higher response rate, there was also a correlation with the increase in clarity regardless of the difficulty level of the questions with Clarity 1.5, 2.0, 2.5, and 3.0. In the participants, however, there is no such increase in parallel with the increase in clarity.

  View details for DOI 10.1016/j.compbiomed.2023.107807

  View details for PubMedID 38091727

• Cytodifferentiation of pituitary tumors influences pathogenesis and cavernous sinus invasion. Journal of neurosurgery Asmaro, K., Zhang, M., Rodrigues, A. J., Mohyeldin, A., Vigo, V., Nernekli, K., Vogel, H., Born, D. E., Katznelson, L., Fernandez-Miranda, J. C. 2023: 1-9

  Abstract

  Pituitary tumors (PTs) continue to present unique challenges given their proximity to the cavernous sinus, whereby invasive behavior can limit the extent of resection and surgical outcome, especially in functional tumors. The aim of this study was to elucidate patterns of cavernoinvasive behavior by PT subtype.A total of 169 consecutive first-time surgeries for PTs were analyzed; 45% of the tumors were functional. There were 64 pituitary transcription factor-1 (PIT-1)-expressing, 62 steroidogenic factor-1 (SF-1)-expressing, 38 T-box transcription factor (TPIT)-expressing, and 5 nonstaining PTs. The gold standard for cavernous sinus invasion (CSI) was based on histopathological examination of the cavernous sinus medial wall and intraoperative exploration.Cavernous sinus disease was present in 33% of patients. Of the Knosp grade 3 and 4 tumors, 12 (19%) expressed PIT-1, 7 (11%) expressed SF-1, 8 (21%) expressed TPIT, and 2 (40%), were nonstaining (p = 0.36). PIT-1 tumors had a significantly higher predilection for CSI: 53% versus 24% and 18% for TPIT and SF-1 tumors, respectively (OR 6.08, 95% CI 2.86-13.55; p < 0.001). Microscopic CSI-defined as Knosp grade 0-2 tumors with confirmed invasion-was present in 44% of PIT-1 tumors compared with 7% and 13% of TPIT and SF-1 tumors, respectively (OR 11.72, 95% CI 4.35-35.50; p < 0.001). Using the transcavernous approach to excise cavernous sinus disease, surgical biochemical remission rates for patients with acromegaly, prolactinoma, and Cushing disease were 88%, 87%, and 100%, respectively. The granule density of PIT-1 tumors and corticotroph functional status did not influence CSI.The likelihood of CSI differed by transcription factor expression; PIT-1-expressing tumors had a higher predilection for invading the cavernous sinus, particularly microscopically, compared with the other tumor subtypes. This elucidates a unique cavernoinvasive behavior absent in cells from other lineages. Innovative surgical techniques, however, can mitigate tumor behavior and achieve robust, reproducible biochemical remission and gross-total resection rates. These findings can have considerable implications on the surgical management and study of PT biology and behavior.

  View details for DOI 10.3171/2023.3.JNS221949

  View details for PubMedID 37119095

• A simple technique for generating 3D endoscopic images. Surgical neurology international Campero, A., Baldoncini, M., Villalonga, J. F., Nernekli, K., Pipolo, D. O., Forlizzi, V., Fernandez-Miranda, J. C. 2023; 14: 54

  Abstract

  Background: Most neurosurgical photographs are limited to two-dimensional (2D), in this sense, most teaching and learning of neuroanatomical structures occur without an appreciation of depth. The objective of this article is to describe a simple technique for obtaining right and left 2D endoscopic images with manual angulation of the optic.Methods: The implementation of a three-dimensional (3D) endoscopic image technique is reported. We first describe the background and core principles related to the methods employed. Photographs are taken demonstrating the principles and also during an endoscopic endonasal approach, illustrating the technique. Later, we divide our process into two sections containing explanations, illustrations, and descriptions.Results: The results of taking a photograph with an endoscope and its assembly to a 3D image has been divided into two parts: Photo acquisition and image processing.Conclusion: We conclude that the proposed method is successful in producing 3D endoscopic images.

  View details for DOI 10.25259/SNI_1106_2022

  View details for PubMedID 36895218