966 results on '"TSC"'
Search Results
2. Regulating Together in Tuberous Sclerosis Complex (RT)
- Author
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United States Department of Defense
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- 2024
3. HtrA4 is well conserved only in higher primates and functionally important for EVT differentiation.
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Wang, Yao, Li, Ying, and Nie, Guiying
- Abstract
The placenta differs greatly among species, and deep extra-villous trophoblast (EVT) invasion is a unique feature of placentation of higher primates including humans. We reported serine protease HtrA4 being found predominantly in human placentas with aberrant expression linked to preeclampsia. However, it remains unclear where HtrA4 is produced in the placenta, how it is expressed in other species, and whether it is essential for human placentation. We first compared HtrA4 protein sequences of over 100 species, then scrutinized the key characteristics of HtrA4 in the human, rhesus macaque and mouse, and determined cellular localization in the placenta. We next investigated functional significance of HtrA4 in EVT differentiation using human trophoblast stem cells (TSCs). Across broader species HtrA4 is well conserved only in higher primates. In humans, only the placenta expressed HtrA4, localising to trophoblasts of villous as well as extra-villous lineages. Rhesus macaques produced HtrA4 but again only in placentas, whereas mice showed no abundant HtrA4 expression anywhere including the placenta, yet it was an active protease if produced. The functional importance of HtrA4 in human EVT was demonstrated using TSCs, which expressed low levels of HtrA4 but significantly up-regulated it during EVT differentiation, and knockdown of HtrA4 severely inhibited the differentiation process. HtrA4 is expressed in placentas of humans and macaques but not mice; it is critical for human EVT differentiation. Together with previous reports showing HtrA4 is also indispensable for syncytialization, this study further revealed HtrA4 as a functionally important protease for human placentation. • HtrA4 protein sequence is well conserved only in higher primates across broad species. • HtrA4 production is absent in mice and limited to placentas in humans and rhesus macaques. • The human placenta expresses HtrA4 in villous as well as extra-villous trophoblasts (EVTs). • Human trophoblast stem cells require HtrA4 to differentiate into EVTs. [ABSTRACT FROM AUTHOR]
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- 2024
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4. TSC Remote Assessment and Intervention (TRAIN)
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Connie Kasari, Ph.D., Professor
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- 2023
5. Challenges of siblings with tuberous sclerosis showing various manifestations and severe complications
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Utami Purbasari, MD, Nurhayati Adnan Prihartono, MPH, MSc, ScD, N Helda, MD, MPH, PhD, Fatira Ratri Audita, MD, and Bobby S Dharmawan, MD, PhD
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TSC ,Siblings renal angiomyolipoma ,SEGA ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that primarily affects the central nervous system and various body organs. This case series describes the case history of 2 siblings from the same parents who were diagnosed with TSC. Case 1 is a 13-year-old girl with bilateral renal AML (angiomyolipoma), multiple fat nodules in the liver, and subependymal nodules with tubers revealed in the brain magnetic resonance imaging (MRI). Case 2 is her brother, a 6-year-old boy, who presented with manifestations of subependymal giant cell astrocytoma (SEGA) and renal AML. TSC must be managed with early diagnosis and intervention due to the risk of hamartoma enlargement. These 2 cases found in siblings underline the varied clinical presentations of TSC and the complexities faced by families with TSC. Early diagnosis is important to avoid TSC-related complications because, as time goes by, the disease will impact the patient's quality of life and increase morbidity and mortality. This case series also highlights the advantages of dermatological screening for the early detection of TSC, family screening, the need for multiple imaging modalities and counseling of family members with TSC, as well as the need for ongoing follow-up of this rare disorder.
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- 2024
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6. Acoustic Detection and Quantification of Fish in Lancang Waters of Seribu Islands, Indonesia.
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Purnawan, Syahrul, Manik, Henry M., Manik, Agustina Sartika, Elson, La, and Myounghee Kang
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Sound propagates effectively through the water column, establishing hydroacoustic technology as a premier method for underwater exploration, including the mapping of aquatic ecological resources. While the fisheries sector is considered pivotal in aquatic resource studies, mapping fisheries remains challenging due to the distinct distribution patterns exhibited by fish within the water column, which are intricately linked to their habitat preferences. In this study, the hydroacoustic method was employed to analyze the distribution of fish in the waters surrounding Lancang Island, Seribu Islands, Jakarta. This analysis utilized the target strength (TS) value alongside oceanographic parameters. Acoustic data was collected using a 200 kHz single beam echosounder based on parallel transects encircling the waters of Lancang Island. CTD was utilized to collect oceanographic data to acquire temperature and salinity profiles within the water column. The acoustic data processing was conducted using the post-processing software SONAR 5-pro. The analysis was performed based on acoustic cells, obtained by dividing segments every 100 m horizontally and layers every 5 m vertically, thereby obtaining the Target Strength per cell (TSc) and volume backscattering strength (SV) values from each cell. The results showed that the highest average TSc value was found in the depth range of 26-31 m at -46.98 dB, and the highest SED biomass was also found in the same depth range at 26.6 kg.ha-1. Based on the analysis of water temperature and salinity, it was found that these factors significantly influence the distribution of fish in the waters of Lancang Island (R-square= 0.1276 and P< 0.05). This finding also indicates the presence of other parameters affecting fish distribution in Lancang waters, with the type of substrate and habitat emerging as potential determining factors, notably in coral reef environments. [ABSTRACT FROM AUTHOR]
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- 2024
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7. SEGA‐like circumscribed astrocytoma in a non‐NF1 patient, harboring molecular profile of GBM. A case report.
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Yamada, Seiji, Tanikawa, Motoki, Matsushita, Yuko, Fujinami, Ryota, Yamada, Hiroshi, Sakomi, Kaishi, Sakata, Tomohiro, Inagaki, Hidehito, Yokoo, Hideaki, Ichimura, Koichi, and Mase, Mitsuhito
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Subependymal giant cell astrocytoma (SEGA) is a low‐grade periventricular tumor that is closely associated with tuberous sclerosis complex (TSC). SEGA typically arises during the first two decades of life and rarely arises after the age of 20–25 years. Nevertheless, it has also been reported that glioma histologically resembling SEGA, so‐called SEGA‐like astrocytoma, can arise in neurofibromatosis type 1 (NF1) patients, even in the elderly. Herein, we report a case of SEGA‐like circumscribed astrocytoma arising in the lateral ventricle of a 75‐year‐old woman. Whole‐exome sequencing revealed a somatic variant of NF1. Methylation array analysis led to a diagnosis of "methylation class glioblastoma, IDH‐wildtype, mesenchymal‐type (GBM, MES)" with a high calibrated score (0.99). EGFR amplification, CDKN2A/B homozygous deletion, chromosomal +7/−10 alterations, and TERT promoter mutation, typical molecular abnormalities usually found in GBM, were also observed. While most reported cases of SEGA‐like astrocytoma have arisen in NF1 patients, the patient was neither TSC nor NF1. Near total removal was accomplished with endoscopic cylinder surgery. At the 36‐month follow‐up, there was no tumor recurrence without adjuvant therapies. This clinical behavior did not match GBM. SEGA‐like astrocytoma of the elderly is rare, and this is the oldest case reported so far. In addition, high‐grade molecular features found in circumscribed tumor remain unclear. Further investigations among larger series are needed for clarifying the underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Prevalence of Liver Steatosis in Tuberous Sclerosis Complex Patients: A Retrospective Cross-Sectional Study.
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De Bock, Thaïs, Brussaard, Carola, François, Silke, François, Karlien, Seynaeve, Laura, Jansen, Anna, Wissing, Karl Martin, and Janssens, Peter
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TUBEROUS sclerosis , *FATTY degeneration , *LIVER , *CROSS-sectional method , *FATTY liver , *BENIGN tumors - Abstract
Introduction: Tuberous sclerosis complex (TSC) is a genetic disease caused by pathogenetic variants in either the TSC1 or TSC2 genes. Consequently, the mechanistic target of the rapamycin complex 1 (mTORC1) pathway, a regulator of cell growth, metabolism, and survival, becomes inappropriately activated, leading to the development of benign tumors in multiple organs. The role of mTORC1 in lipid metabolism and liver steatosis in TSC patients has not been well-studied, and clinical data on liver involvement in this population are scarce. Methods: We conducted a retrospective, cross-sectional study to compare liver steatosis in TSC patients with age-, sex-, BMI-, and diabetes status-matched controls. Participants with a definite diagnosis of TSC were recruited from the TSC clinic at UZ Brussel. Liver steatosis was quantified using the fat signal fraction from in-phase and out-of-phase MRI, with a threshold of ≥5% defining the presence of steatosis. We also evaluated the prevalence of liver angiomyolipomata in the TSC group and analyzed risk factors for both liver steatosis and angiomyolipomata. Results: The study included 59 TSC patients and 59 matched controls. The mean fat signal fraction was 4.0% in the TSC group and 3.9% in the controls, showing no significant difference (two-tailed Wilcoxon signed ranks test, p = 0.950). Liver steatosis was observed in 15.3% of TSC patients compared to 23.7% of the controls, which was not statistically significant (two-tailed McNemar test, p = 0.267). Liver angiomyolipomata were identified in 13.6% of the TSC cohort. Conclusions: Our study, describing in detail the liver phenotype of TSC patients, did not reveal a significant difference in the prevalence of MRI-assessed liver steatosis in a large cohort of TSC patients compared to a closely matched control group. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Concordance of MTOR Pathway Mutations and the Diagnosis of Renal Low-Grade Oncocytic Tumor (LOT).
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Siegmund, Stephanie E., Al-Obaidy, Khaleel I., Tsai, Harrison K., Idrees, Muhammad T., Akgul, Mahmut, Acosta, Andres M., and Hirsch, Michelle S.
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KIDNEY tumors , *RENAL cell carcinoma , *NUCLEOTIDE sequencing , *DIAGNOSIS , *TUMORS - Abstract
The differential diagnosis for oncocytic renal tumors spans the spectrum from benign entities to more aggressive renal cell carcinomas (RCC). Recent work has characterized a provisional renal oncocytic neoplasm, namely the low-grade oncocytic tumor (LOT), which demonstrates overlapping morphologic features with oncocytoma and chromophobe RCC, but also has a unique immunoprofile (ie, diffusely positive for KRT7, negative for KIT) and a high rate (80% to 100%) of mTOR pathway gene alterations. Given the diagnostic overlap among oncocytic tumors, we looked for concordance between mTOR pathway mutations and LOT. Thirty low-grade renal oncocytic neoplasms underwent histologic review and immunohistochemistry for KRT7 and KIT. Tumors were classified as "determinate" (eg, LOT) for tumors with solid, nested or vaguely tubular growth and diffuse KRT7 staining and negative KIT, or "indeterminate" if the morphology and/or immunostains did not fully support a definitive LOT diagnosis. Next-generation sequencing was performed without any knowledge of the diagnoses, and identified mTOR pathway mutations in 80% (12/15) of the determinate tumors, compared with 7% (1/15) in the indeterminate group. One determinate tumor was reclassified as papillary RCC (MTOR mutation negative) and 6 indeterminate tumors were confirmed to be oncocytoma (N = 4), clear cell RCC or papillary RCC with reverse polarity, respectively. Overall, integration of morphology, immunohistochemistry, and molecular data enabled a final definitive diagnosis for 70% of tumors (21 of the total 30), with a high concordance (93%) for LOT specifically in the determinate group; the remaining 9 tumors (30%) were classified as renal oncocytic neoplasm, not otherwise specified. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Targeting the EGFR pathway: An alternative strategy for the treatment of tuberous sclerosis complex?
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Schachenhofer, Julia, Gruber, Victoria‐Elisabeth, Fehrer, Stefanie Valerie, Haider, Carmen, Glatter, Sarah, Liszewska, Ewa, Höftberger, Romana, Aronica, Eleonora, Rössler, Karl, Jaworski, Jacek, Scholl, Theresa, and Feucht, Martha
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TUBEROUS sclerosis , *FOCAL cortical dysplasia , *EPIDERMAL growth factor receptors - Abstract
Introduction: Tuberous sclerosis complex (TSC) is caused by variants in TSC1/TSC2, leading to constitutive activation of the mammalian target of rapamycin (mTOR) complex 1. Therapy with everolimus has been approved for TSC, but variations in success are frequent. Recently, caudal late interneuron progenitor (CLIP) cells were identified as a common origin of the TSC brain pathologies such as subependymal giant cell astrocytomas (SEGA) and cortical tubers (CT). Further, targeting the epidermal growth factor receptor (EGFR) with afatinib, which is expressed in CLIP cells, reduces cell growth in cerebral TSC organoids. However, investigation of clinical patient‐derived data is lacking. Aims: Observation of EGFR expression in SEGA, CT and focal cortical dysplasia (FCD) 2B human brain specimen and investigation of whether its inhibition could be a potential therapeutic intervention for these patients. Methods: Brain specimens of 23 SEGAs, 6 CTs, 20 FCD2Bs and 17 controls were analysed via immunohistochemistry to characterise EGFR expression, cell proliferation (via Mib1) and mTOR signalling. In a cell‐based assay using primary patient‐derived cells (CT n = 1, FCD2B n = 1 and SEGA n = 4), the effects of afatinib and everolimus on cell proliferation and cell viability were observed. Results: EGFR overexpression was observed in histological sections of SEGA, CT and FCD2B patients. Both everolimus and afatinib decreased the proliferation and viability in primary SEGA, tuber and FCD2B cells. Conclusion: Our study demonstrates that EGFR suppression might be an effective alternative treatment option for SEGAs and tubers, as well as other mTOR‐associated malformations of cortical development, including FCD2B. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Case Report: Patent ductus arteriosus with tuberous sclerosis complex
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Tingrui Chen, Xiaoxiao Wu, and Yiping Wang
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patent ductus arteriosus ,tuberous sclerosis complex ,gene ,ICU ,TSC ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
A 33-year-old patient presented with a chief complaint of patent ductus arteriosus (PDA) persisting for over 30 years. Physical examination revealed bilateral facial angiofibromas, multiple nail fibromas, intraoral fibromas, and a ’shagreen patch’ on the left lumbar region. Genetic testing was performed using a peripheral venous blood sample, which confirmed the diagnosis of Tuberous Sclerosis Type 2 (TSC2). Subsequently, the patient underwent cardiac color Doppler ultrasound and chest computed tomography angiography, which confirmed the presence of PDA. Tuberous sclerosis complex (TSC) is associated with cardiovascular diseases. The initial clinical manifestation of TSC is usually cardiac rhabdomyoma in children, and it is rarely reported in adults with PDA. In this case, the patient was diagnosed with PDA when he was young, and the genetic test showed heterozygous variation of TSC2 gene. The purpose of this article is to explore the correlation between TSC and PDA at the gene level through literature review.
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- 2024
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12. TSC1 splicing mutation in renal angiomyolipoma with epithelial cysts without fat: A very rare case report and literature review
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Qiushi Xu, Liying Yin, Juan Tao, and Fang Peng
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Angiomyolipoma ,Epithelial cysts ,No fat ,TSC ,Case report ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
Renal angiomyolipoma is a benign mesenchymal tumor that can be divided into classical and other subtypes. Angiomyolipoma with epithelial cysts (AMLEC) is an extremely rare non classical subtype. AMLEC without fat component is even rarer. We report a case of AMLEC without fat in a 29-year-old man who was provisionally diagnosed with cystic renal carcinoma by ultrasonography, abdominal enhanced CT and MRI. He had no complaints, or personal or family history of TSC, or other malignancies. Based on imaging findings, robot-assisted laparoscopic nephron-sparing partial nephrectomy through a retroperitoneal approach was performed for the purpose of both diagnosis and treatment. We diagnosed AMLEC after considering the differential diagnosis of other cystic renal neoplasms, such as cystic renal carcinoma, multilocular cystic renal cell neoplasm of low malignant potential, adult cystic nephroma and mixed epithelium and stromal tumor. Meanwhile, the whole-exon sequencing (WES) results showed insert-splicing mutation in the 21st exon and 20th exon of the TSC1 gene. No treatments were performed after the operation and no evidence of recurrence or metastasis at regular follow-up.
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- 2024
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13. HtrA4 is required for human trophoblast stem cell differentiation into syncytiotrophoblast.
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Thach, Bothidah, Wang, Yao, Heng, Sophea, and Nie, Guiying
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The syncytiotrophoblast (STB) of the human placenta facilitates vital maternal-fetal communication and is maintained by fusion (syncytialization) of cytotrophoblasts. Serine protease HtrA4 (high temperature requirement factor A4) is highly expressed only in the human placenta and was previously reported to be important for BeWo fusion. This study investigated whether HtrA4 is critical for differentiation of human trophoblast stem cells (TSCs) into STB. Primary TSCs were isolated from first trimester placentas (n = 5) and validated by immunofluorescence (IF) for CD49f, CK7 and vimentin. TSCs were then differentiated into STB and the success of syncytialization was confirmed by RT-PCR, IF and ELISA of known markers. TSCs were next stably transfected with a HtrA4-targetting CRISPR/Cas9 plasmid, and cells with severe HtrA4 knockdown (HtrA4-KD) were analyzed to investigate the impact on STB differentiation. Primary TSCs were confirmed to be of high purity by staining positively for CD49f and CK7 but negatively for vimentin. These TSCs readily syncytialized when stimulated for STB differentiation, significantly increasing β-hCG and syncytin-1, substantially decreasing E-cadherin, and markedly losing cell borders. While TSCs produced very low levels of HtrA4, upon stimulation for STB differentiation the cells drastically upregulated HtrA4 expression; secretion of HtrA4 protein also increased sharply, correlating positively and significantly with that of β-hCG. The HtrA4-KD TSCs, however, failed to show this surge of HtrA4 production upon stimulation, and ultimately remained primarily mononucleated with no significant STB differentiation. This study demonstrates that HtrA4 plays a critical role in TSC differentiation into syncytiotrophoblast. • HtrA4 expression is significantly upregulated during TSC differentiation into STB. • Secretion of HtrA4 and β-hCG correlates positively and significantly during STB differentiation. • Knockdown of HtrA4 inhibits TSC differentiation into STB. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Bibliometric analysis and network visualization on Tuberous Sclerosis Complex.
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Zulkipli, Ninie Nadia, Long, Idris, Wahab, Habibah A., Sasongko, Teguh Haryo, Ahmad, Asma Hayati, Othman, Zahiruddin, Ahmi, Aidi, and Zakaria, Rahimah
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TUBEROUS sclerosis , *BIBLIOMETRICS , *DATA visualization , *PEDIATRIC neurology , *INTELLECTUAL disabilities , *NEUROBEHAVIORAL disorders - Abstract
Background: Tuberous sclerosis complex (TSC) is a rare autosomal dominant multisystem disease resulting from hyperactivation of the mammalian target of rapamycin (mTOR) signaling pathway. This study aimed to measure the quantitative impact of publications in TSC. Materials and methods: We analysed TSC literature obtained from the Scopus database using Bibliometrix R Package and VOSviewer software. Annual publication trends, most productive and collaborative authors/institutions/countries, most cited articles, most popular journals and author's keywords were presented using standard bibliometric indicators. Results and discussion: A total of 5375 documents on TSC were published from 1960 to December 2020, with an increasing trend. The three primary contributing writers were Curatolo P, Kwiatkowski DJ, and Thiele EA, with the United States and its institutions being the largest contributor. The research identified two of the most referenced papers as TSC's seminal pieces. The top journals that published TSC research were medical journals, namely Journal of Child Neurology, Epilepsia, and Pediatric Neurology. mTOR inhibitor, everolimus, sirolimus, mTORC1, mTOR pathway, autophagy, inflammation, infant, intellectual disability, white matter, TSC-associated neuropsychiatric disorders, TOSCA and quality of life were relatively newer author's keywords and may indicate the future research hotspots in TSC research. Conclusion: Over the last few decades, TSC research has grown in importance, particularly in the field of clinical medicine. Therapeutic components targeting TSC-related pathways, the utilisation of TSC as disease models and long-term safety studies will be future research areas. [ABSTRACT FROM AUTHOR]
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- 2024
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15. A 28-year-old patient with tuberous sclerosis associated with renal angiomyolipoma:A rare case report and literature review
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Hasan Haydar, Mouhammed Sleiay, Mohammed Alqreea, Ahmad Almohamed, Doaa Alrajab, Malak alsaleh, and Mohamad Yasin Lutfi
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Renal angiomyolipoma ,Tubersclerosis ,Renal mass ,TSC ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Tuberous sclerosis complex (TSC) is a genetically inherited disorder distinguished by the development of numerous benign neoplasms across multiple organ systems.Renal angiomyolipoma represents 0.3% of all primary renal tumors and are classified as benign mixed mesenchymal neoplasms. In this report, we reported the clinical presentation of a 28-year-old individual who was received by the department of urology. The patient was admitted presenting with asymptomatic, macroscopic hematuria that had been ongoing for a period of 10 days. Subsequent diagnostic evaluations revealed an association between the presenting urinary condition and tuberous sclerosis complex with a concurrent renal angiomyolipom
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- 2024
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16. Neuropsychiatric comorbidities in tuberous sclerosis complex patients with epilepsy: results of the TAND checklist survey
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Lee, Hom-Yi, Lin, Chien-Heng, Wang, Xing-An, and Tsai, Jeng-Dau
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- 2024
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17. Heat Loads Mitigation Investigation for Divertor Targets in a High Magnetic Field Compact Tokamak.
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Xi, Xuyao, Yang, Jinhong, Chu, Delin, Wang, Weihua, and Chen, Kaijie
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The high magnetic field compact high-temperature superconducting tokamaks are characterized by high energy density, macroscopic instabilities, and high threshold values, which are beneficial to the operation of the device with high parameters, however, this also directly leads to a sharp increase in the heat loads of the divertors. Therefore, in this paper, with reference to the design parameters of SPARC, the TSC is used to simulate the double-null divertor sweeping configuration discharge process of a high magnetic field compact tokamak device (HFCT), and the heat flux distribution on the surface of the target at the time of divertor outer long-leg sweeping in the discharge flat-top stage is obtained, with the peak value of 23.2 MW/m
2 ; both water-cooled monoblock and all-tungsten divertor configurations calculated using ANSYS, which concluded that the tungsten armor thickness d in the all-tungsten divertor configuration should not be greater than 2.5 mm to withstand a peak heat flux of 23.2 MW/m2 ; on the basis of this configuration, the temperature field of the divertor target is calculated for different sweeping fields and the feasibility of the all-tungsten divertor target model is analyzed. This study can be used as a reference for the design of divertor target in future HFCT. [ABSTRACT FROM AUTHOR]- Published
- 2023
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18. Expression profiles of α-synuclein in cortical lesions of patients with FCD IIb and TSC, and FCD rats.
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Li Zhang, Jun Huang, Lu Dai, Gang Zhu, Xiao-Lin Yang, Zeng He, Yu-Hong Li, Hui Yang, Chun-Qing Zhang, Kai-Feng Shen, and Ping Liang
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ALPHA-synuclein ,FOCAL cortical dysplasia ,TUBEROUS sclerosis ,EPILEPSY ,RATS ,METHYL aspartate receptors - Abstract
Background: Focal cortical dysplasia (FCD) IIb and tuberous sclerosis complex (TSC) are common causes of drug-resistant epilepsy in children. However, the etiologies related to the development of FCD IIb and TSC are not fully understood. α-synuclein (α-syn) is a member of synucleins family that plays crucial roles in modulating synaptic transmission in central nervous system.Here, we explored the expression profiles and potential pathogenic functions of a-syn in cortical lesions of epileptic patients with FCD IIb and TSC. Methods: Surgical specimens fromepileptic patients with FCD IIb and TSC, as well as FCD rats generated by in utero X-ray-radiation were adopted in this study and studied with immunohistochemistry, immunofluorescence, western blotting, and co-immunoprecipitation etc. molecular biological techniques. Result: Our results showed that α-syn expression was reduced in FCD IIb and TSC lesions. Specifically, α-syn protein was intensely expressed in dysplastic neurons (DNs) and balloon cells (BCs) in FCD IIb lesions, whereas was barely detected in DNs and giant cells (GCs) of TSC lesions. Additionally, p-α-syn, the aggregated formof α-syn, was detected inDNs, BCs,GCs, and glia-like cells of FCDIIb and TSC lesions. We previous showed that the function of N-methyl-D-aspartate receptor (NMDAR) was enhanced in FCD rats generated by X-ray-radiation. Here, we found the interaction between α-syn and NMDAR subunits NMDAR2A, NMDAR2B were augmented in cortical lesions of FCD patients and FCD rats. Conclusion: These results suggested a potential role of α-syn in the pathogenesis of FCD IIb and TSC by interfering with NMDAR. [ABSTRACT FROM AUTHOR]
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- 2023
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19. Long-Term Outcomes of Tuberous Sclerosis Complex-Associated Non-functional Pancreatic Neuroendocrine Tumors: Should We Be More Conservative?
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Arya, Shahrzad, Ventin, Marco, Nebbia, Martina, Fernandez-del Castillo, Carlos, Lionetto, Gabriella, Qadan, Motaz, Lillemoe, Keith D., Deshpande, Vikram, Catalano, Onofrio A., Thiele, Elizabeth A., and Ferrone, Cristina R.
- Abstract
Background: Hereditary syndromes such as tuberous sclerosis complex (TSC) account for 10% of pancreatic neuroendocrine tumors (PNETs). Surgical intervention is the current standard of care for sporadic PNETs (spPNETs) that are >2 cm in size. We compared the long-term outcomes of resected TSC-PNETs with patients with spPNETs. Methods: We conducted a retrospective review of perioperative data and outcomes of TSC-PNETs compared with spPNETs. Inclusion criteria involved selecting patients whose tumors were no larger than 5.1 cm, the maximum size observed in the TSC-PNET group. Results: Of the 347 patients resected for PNETs, 14 were TSC-PNETs and 241 were non-functional spPNETs. The median age for the whole cohort was 56 years (interquartile range [IQR] 21.0) and 47% were female. The median follow-up was 103.8 months (95% confidence interval [CI] 89.2–118.6). Specifically, 14 patients with TSC-PNETs and 194 patients with spPNETs were included. Compared with spPNETs, patients with TSC-PNETs were operated on at a younger age (24.0 vs. 57.5 years; p < 0.001), were more frequently multifocal (28.5% vs. 0.0%; p < 0.001), were more likely to undergo minimally invasive operations (78.6% vs. 24.3%; p < 0.001), and had more R1 resections (28.6% vs. 5.7%; p = 0.006). Local and distant tumor recurrence was only observed in the spPNET group. The 5-year mortality rates for the spPNET and TSC-PNET groups were 6.2% and 0.0%, respectively. No PNET-related deaths were observed among TSC-PNETs. Conclusion: None of the TSC-PNET patients recurred after a median follow-up of 78.0 months. The risk-benefit of aggressive pancreatic operations in TSC-PNET patients is still unclear and our findings suggest a conservative approach should be considered. [ABSTRACT FROM AUTHOR]
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- 2023
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20. Cystic kidney disease in tuberous sclerosis complex: current knowledge and unresolved questions.
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Gallo-Bernal, Sebastian, Kilcoyne, Aoife, Gee, Michael S., and Paul, Elahna
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KIDNEY physiology , *HYPERTENSION risk factors , *PUBLIC health surveillance , *PROTEIN kinases , *GENETIC mutation , *SIGNAL peptides , *CELL physiology , *RISK assessment , *TUMOR suppressor genes , *KIDNEY tumors , *CYSTIC kidney disease , *TUBEROUS sclerosis , *DISEASE risk factors , *DISEASE complications - Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with an estimated incidence of one in 5000 to 10,000 live births worldwide. Two million people of all races and genders are estimated to have TSC secondary to mutations in one of two tumor suppressor genes, TSC1 or TSC2. The respective TSC1 and 2 gene products — hamartin and tuberin — form cytoplasmic heterodimers that inhibit mTOR-mediated cell growth and division. When mTOR inhibition is lost, people with TSC develop characteristic and usually benign tumors in various organ systems. Kidney tumors and cysts are common, particularly in the setting of TSC2 gene mutations. In most TSC patients, the number of kidney cysts is limited, their morphology is simple, their size is small, and their clinical significance is negligible. In some, cyst morphology progresses from simple to complex with the risk of malignant transformation. In others, aggressive accumulation and growth of kidney cysts can cause hypertension, impaired kidney function, and progression to kidney failure. This educational review summarizes current knowledge and remaining open questions regarding cystic kidney disease in TSC, emphasizing detection, classification, surveillance, and treatment options. [ABSTRACT FROM AUTHOR]
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- 2023
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21. Ocena procesu regeneracji nerwu kulszowego mysiego modelu zwierzęcego po zastosowaniu uszkodzenia metodą mrożenia, zmiażdżenia lub elektrokoagulacji.
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Górka, Dariusz, Suszyński, Krzysztof, Białoń, Natalia, Górka, Mikołaj, Trzęsicki, Michał, Zając, Kacper, Dolińska, Anna, and Tomsia, Filip
- Abstract
Copyright of Advances in Biochemistry / Postepy Biochemii is the property of Polish Biochemical Society / Acta Biochimica Polonica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2023
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22. Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2
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Kosillo, Polina, Ahmed, Kamran M, Aisenberg, Erin E, Karalis, Vasiliki, Roberts, Bradley M, Cragg, Stephanie J, and Bateup, Helen S
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Neurosciences ,Underpinning research ,1.1 Normal biological development and functioning ,Animals ,Dopamine ,Dopaminergic Neurons ,Mechanistic Target of Rapamycin Complex 1 ,Mechanistic Target of Rapamycin Complex 2 ,Mice ,TOR Serine-Threonine Kinases ,mTORC1 ,mTORC2 ,raptor ,rictor ,dopamine neurons ,TSC ,Mouse ,mouse ,neuroscience ,Biochemistry and Cell Biology - Abstract
The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTORC2. How each of these complexes affect dopamine neuron properties, and whether they have similar or distinct functions is unknown. Here, we investigated this in mice with dopamine neuron-specific deletion of Rptor or Rictor, which encode obligatory components of mTORC1 or mTORC2, respectively. We find that inhibition of mTORC1 strongly and broadly impacts dopamine neuron structure and function causing somatodendritic and axonal hypotrophy, increased intrinsic excitability, decreased dopamine production, and impaired dopamine release. In contrast, inhibition of mTORC2 has more subtle effects, with selective alterations to the output of ventral tegmental area dopamine neurons. Disruption of both mTOR complexes leads to pronounced deficits in dopamine release demonstrating the importance of balanced mTORC1 and mTORC2 signaling for dopaminergic function.
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- 2022
23. Defining the Magnetic Resonance Features of Renal Lesions and Their Response to Everolimus in a Transgenic Mouse Model of Tuberous Sclerosis Complex
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Agarwal, Shubhangi, Decavel-Bueff, Emilie, Wang, Yung-Hua, Qin, Hecong, Santos, Romelyn Delos, Evans, Michael J, and Sriram, Renuka
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Tuberous Sclerosis ,Biomedical Imaging ,Cancer ,Kidney Disease ,Brain Disorders ,TSC ,kidney ,everolimus ,mTOR ,MRI ,mp-MRI ,AML ,Clinical sciences ,Oncology and carcinogenesis - Abstract
Tuberous sclerosis complex (TSC) is an inherited genetic disorder characterized by mutations in TSC1 or TSC2 class of tumor suppressers which impact several organs including the kidney. The renal manifestations are usually in the form of angiomyolipoma (AML, in 80% of the cases) and cystadenomas. mTOR inhibitors such as rapamycin and everolimus have shown efficacy in reducing the renal tumor burden. Early treatment prevents the progression of AML; however, the tumors regrow upon cessation of therapy implying a lifelong need for monitoring and management of this morbid disease. There is a critical need for development of imaging strategies to monitor response to therapy and progression of disease which will also facilitate development of newer targeted therapy. In this study we evaluated the potential of multiparametric 1H magnetic resonance imaging (mpMRI) to monitor tumor response to therapy in a preclinical model of TSC, the transgenic mouse A/J Tsc2+/- . We found 2-dimensional T2-weighted sequence with 0.5 mm slice thickness to be optimal for detecting renal lesions as small as 0.016 mm3. Baseline characterization of lesions with MRI to assess physiological parameters such as cellularity and perfusion is critical for distinguishing between cystic and solid lesions. Everolimus treatment for three weeks maintained tumor growth at 36% from baseline, while control tumors displayed steady growth and were 70% larger than baseline at the end of therapy. Apparent diffusion coefficient, T1 values and normalized T2 intensity changes were also indictive of response to treatment. Our results indicate that standardization and implementation of improved MR imaging protocols will significantly enhance the utility of mpMRI in determining the severity and composition of renal lesions for better treatment planning.
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- 2022
24. A Cryogenic System for Measuring the Thermally Stimulated Depolarization Current
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Yan, Jixiang, Huang, Rongjin, Jia, Peng, Liu, Huiming, Shi, Yaran, Xie, Shiyong, Li, Laifeng, Zhou, Yuan, Qiu, Limin, editor, Wang, Kai, editor, and Ma, Yanwei, editor
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- 2023
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25. Polycystic Kidney Disease: ADPKD and ARPKD
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Liebau, Max Christoph, Mekahli, Djalila, Bergmann, Carsten, Schaefer, Franz, editor, and Greenbaum, Larry A., editor
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- 2023
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26. Predictive Model for Depression and Anxiety Using Machine Learning Algorithms
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Jha, Anmol, Abirami, M. S., Kumar, Vishal, Filipe, Joaquim, Editorial Board Member, Ghosh, Ashish, Editorial Board Member, Prates, Raquel Oliveira, Editorial Board Member, Zhou, Lizhu, Editorial Board Member, Kottursamy, Kottilingam, editor, Bashir, Ali Kashif, editor, Kose, Utku, editor, and Uthra, Annie, editor
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- 2023
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27. Rhabdomyoma
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Al-Obaidi, Mustafa Najah, Al-Obaidi, Ahmed Dheyaa, Ahmad, Shkaib, Ali, Abeer Mundher, Ahmad, Sara Shihab, Tagarakis, Georgios, editor, Gheni Sarfan, Ahmed, editor, Hashim, Hashim Talib, editor, and Varney, Joseph, editor
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- 2023
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28. Harnessing rare variants in neuropsychiatric and neurodevelopment disorders—a Keystone Symposia report
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Cable, Jennifer, Purcell, Ryan H, Robinson, Elise, Vorstman, Jacob AS, Chung, Wendy K, Constantino, John N, Sanders, Stephan J, Sahin, Mustafa, Dolmetsch, Ricardo E, Shah, Bina Maniar, Thurm, Audrey, Martin, Christa L, Bearden, Carrie E, and Mulle, Jennifer G
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Human Genome ,Intellectual and Developmental Disabilities (IDD) ,Autism ,Pediatric ,Mental Health ,Neurosciences ,Schizophrenia ,Behavioral and Social Science ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Mental health ,Congresses as Topic ,Genetic Variation ,Humans ,Mental Disorders ,Neurodevelopmental Disorders ,Penetrance ,Research Report ,autism ,autism heterogeneity ,autism spectrum disorder ,copy number variant ,intellectual disability ,neurodevelopmental disorders ,neuropsychiatric disorders ,polygenic risk score ,rare variants ,schizophrenia ,3q29 deletion ,TSC ,16p11 ,deletion ,22q11 ,16p11.2 deletion ,22q11.2 deletion ,General Science & Technology - Abstract
Neurodevelopmental neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, have strong genetic risk components, but the underlying mechanisms have proven difficult to decipher. Rare, high-risk variants may offer an opportunity to delineate the biological mechanisms responsible more clearly for more common idiopathic diseases. Indeed, different rare variants can cause the same behavioral phenotype, demonstrating genetic heterogeneity, while the same rare variant can cause different behavioral phenotypes, demonstrating variable expressivity. These observations suggest convergent underlying biological and neurological mechanisms; identification of these mechanisms may ultimately reveal new therapeutic targets. At the 2021 Keystone eSymposium "Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants" a panel of experts in the field described significant progress in genomic discovery and human phenotyping and raised several consistent issues, including the need for detailed natural history studies of rare disorders, the challenges in cohort recruitment, and the importance of viewing phenotypes as quantitative traits that are impacted by rare variants.
- Published
- 2021
29. Prevalence of Liver Steatosis in Tuberous Sclerosis Complex Patients: A Retrospective Cross-Sectional Study
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Thaïs De Bock, Carola Brussaard, Silke François, Karlien François, Laura Seynaeve, Anna Jansen, Karl Martin Wissing, and Peter Janssens
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TSC ,mTOR ,liver steatosis ,liver angiomyolipomata ,MRI ,Medicine - Abstract
Introduction: Tuberous sclerosis complex (TSC) is a genetic disease caused by pathogenetic variants in either the TSC1 or TSC2 genes. Consequently, the mechanistic target of the rapamycin complex 1 (mTORC1) pathway, a regulator of cell growth, metabolism, and survival, becomes inappropriately activated, leading to the development of benign tumors in multiple organs. The role of mTORC1 in lipid metabolism and liver steatosis in TSC patients has not been well-studied, and clinical data on liver involvement in this population are scarce. Methods: We conducted a retrospective, cross-sectional study to compare liver steatosis in TSC patients with age-, sex-, BMI-, and diabetes status-matched controls. Participants with a definite diagnosis of TSC were recruited from the TSC clinic at UZ Brussel. Liver steatosis was quantified using the fat signal fraction from in-phase and out-of-phase MRI, with a threshold of ≥5% defining the presence of steatosis. We also evaluated the prevalence of liver angiomyolipomata in the TSC group and analyzed risk factors for both liver steatosis and angiomyolipomata. Results: The study included 59 TSC patients and 59 matched controls. The mean fat signal fraction was 4.0% in the TSC group and 3.9% in the controls, showing no significant difference (two-tailed Wilcoxon signed ranks test, p = 0.950). Liver steatosis was observed in 15.3% of TSC patients compared to 23.7% of the controls, which was not statistically significant (two-tailed McNemar test, p = 0.267). Liver angiomyolipomata were identified in 13.6% of the TSC cohort. Conclusions: Our study, describing in detail the liver phenotype of TSC patients, did not reveal a significant difference in the prevalence of MRI-assessed liver steatosis in a large cohort of TSC patients compared to a closely matched control group.
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- 2024
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30. Loss of maturity and homeostatic functions in Tuberous Sclerosis Complex-derived astrocytes
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Mark J. Luinenburg, Mirte Scheper, Frederik N. F. Sørensen, Jasper J. Anink, Wim Van Hecke, Irina Korshunova, Floor E. Jansen, Kate Riney, Pieter van Eijsden, Peter Gosselaar, James D. Mills, Rozemarijn S. Kalf, Till S. Zimmer, Diede W. M. Broekaart, Konstantin Khodosevich, Eleonora Aronica, and Angelika Mühlebner
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astrocytes ,inflammation ,phagocytosis ,glutamate buffering ,TSC ,epilepsy ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
IntroductionConstitutive activation of the mTOR pathway, as observed in Tuberous Sclerosis Complex (TSC), leads to glial dysfunction and subsequent epileptogenesis. Although astrocytes are considered important mediators for synaptic clearance and phagocytosis, little is known on how astrocytes contribute to the epileptogenic network.MethodsWe employed singlenuclei RNA sequencing and a hybrid fetal calf serum (FCS)/FCS-free cell culture model to explore the capacity of TSC-derived astrocytes to maintain glutamate homeostasis and clear debris in their environment.ResultsWe found that TSC astrocytes show reduced maturity on RNA and protein level as well as the inability to clear excess glutamate through the loss of both enzymes and transporters complementary to a reduction of phagocytic capabilities.DiscussionOur study provides evidence of mechanistic alterations in TSC astrocytes, underscoring the significant impairment of their supportive functions. These insights enhance our understanding of TSC pathophysiology and hold potential implications for future therapeutic interventions.
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- 2023
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31. A Roadmap for ROK-US-Japan Trilateral Security Cooperation (TSC).
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Alex Soohoon Lee
- Abstract
In the face of increasing security threats in the Indo-Pacific, and especially those by the DPRK, trilateral security cooperation (TSC) among the Republic of Korea, the United States, and Japan is imperative to sustain peace and stability in the region. The Camp David Summit, in this regard, has established a formal cooperative mechanism and produced meaningful trilateral agendas. Over the last several decades, the three nations have made several attempts to form cooperation but failed at every attempt. This research analyzes the brief history of trilateral cooperation between the Republic of Korea, the United States, and Japan and proposes a way to make this cooperation more sustainable. The key to increasing the mechanism's sustainability would be the institutionalization of agendas. In light of this, the research employs a norm life-cycle, presented by Finnemore and Sikkink, to assess the agendas discussed at Camp David at the August 2023 summit. Ultimately, the manuscript draws a roadmap for the TSC that the three countries' governments can refer to. [ABSTRACT FROM AUTHOR]
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- 2023
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32. Szlak mTOR i zwierzęta transgeniczne z delecją genu TSC w procesie regeneracji układu nerwowego i wybranych modelach uszkodzeń nerwu kulszowego.
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Białoń, Natalia, Suszyński, Krzysztof, Górka, Mikołaj, Trzęsicki, Michał, Górka, Dariusz, Zając, Kacper, and Kupczak, Agata
- Subjects
NEURONS ,NERVOUS system ,NERVE fibers ,SCIATIC nerve ,NERVOUS system regeneration ,WNT signal transduction - Abstract
Copyright of Advances in Biochemistry / Postepy Biochemii is the property of Polish Biochemical Society / Acta Biochimica Polonica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2023
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33. Novel Zero Circular Convolution Sequences for Detection and Channel Estimations
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Donghua Xuan, Ho-Hsuan Chang, and Gaofei Huang
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FSC ,PACF ,PCCF ,PGIS ,TSC ,ZCC sequences ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 - Abstract
Multiuser communication systems or multiple access scheme systems favor sequences possessing the ideal periodic cross-correlation function (PCCF) property. In comparison, channel estimation, equalization, and synchronization applications favor sequences possessing the ideal periodic auto-correlation function (PACF) property. However, there is no set of sequences possessing both the ideal PCCF and PACF properties simultaneously, where auto-correlation and cross-correlation balance each other. In this work, sequences possessing the ideal PACF property are used as the base sequences. Then, a modulation technique is applied upon these base sequences to construct a set of zero circular convolution (ZCC) sequences within which an arbitrary pair of two sequences possesses the ideal PCCF property. Compared with least squares (LS) and minimum mean squared error (MMSE) algorithm, the simulation results show that the channel estimation performance of ZCC is better than MMSE and LS algorithms, and the computational complexity of the algorithm is the same as LS algorithm, but far lower than MMSE algorithm. This is the first study on ZCC sequences reported in the literature, in which their fundamental theorems, properties, construction, and applications are investigated. The advantage of possessing the desired PACF and the ideal PCCF properties allows the ZCC sequences to be used in a broader range of applications than other sets of sequences.
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- 2023
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34. Multi-center Clinical Study on the Diagnosis and Treatment Management of Rare Neurological Disease in Children
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Shanghai Children's Medical Center and Xinhua Hospital of Shanghai Jiaotong University
- Published
- 2021
35. Insulinoma in pediatric tuberous sclerosis complex: a case report
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Katia Librandi, Serena Grimaldi, Silvia Catalano, Francesco Moro, Stefano Gabriele Vallero, Marco Spada, and Francesco Porta
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tuberous sclerosis complex (TSC) ,insulinoma ,TSC ,oncology ,PNET ,Pediatrics ,RJ1-570 - Abstract
BackgroundTuberous sclerosis complex (TSC) is a rare multisystemic disorder. This genetically determined disease is characterized by highly variable clinical expression, including epilepsy as a common feature. Seizures can also occur as a manifestation of symptomatic hypoglycemia. The latter could be caused by an insulinoma, whose association to TSC has already been debated. In TSC-associated tumors, dysregulation of the mTOR pathway is believed to be present, leading to significant impacts on cellular metabolism, growht, and proliferation. To date, the association between TSC and insulinoma has been reported in 11 adults. Here, we present the first case of a pediatric patient with TSC diagnosed with an insulinoma and review the existing literature on this topic.Case presentationA 11-year-old female with TSC presented with seizures unresponsive to standard therapy. Further investigation revealed that these seizures were caused by hypoglycemia. Subsequent evaluation led to the diagnosis of a pancreatic insulinoma, which was surgically removed. Following the procedure, the patient was free from seizures.ConclusionsIn individuals with TSC, the recurrence of epileptiform episodes throughout their lifetime, especially if previously well controlled with antiepileptic therapy, should raise suspicion for hypoglycemic events. These events may potentially be associated with the presence of an insulinoma. Further research and increased awareness are necessary to gain a better understanding of the association between TSC and insulinomas, and to guide clinical management strategies.
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- 2023
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36. Real‐world data on cannabidiol treatment of various epilepsy subtypes: A retrospective, multicenter study.
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Kühne, Fabienne, Becker, Lena‐Luise, Bast, Thomas, Bertsche, Astrid, Borggraefe, Ingo, Boßelmann, Christian Malte, Fahrbach, Jörg, Hertzberg, Christoph, Herz, Nina A., Hirsch, Martin, Holtkamp, Martin, Janello, Christine, Kluger, Gerhard Josef, Kurlemann, Gerhard, Lerche, Holger, Makridis, Konstantin L., von Podewils, Felix, Pringsheim, Milka, Schubert‐Bast, Susanne, and Schulz, Juliane
- Abstract
Objective: Cannabidiol (CBD) is approved for treatment of Dravet syndrome (DS), Lennox‐Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). Several studies suggest antiseizure effects also beyond these three epilepsy syndromes. Methods: In a retrospective multicenter study, we analyzed the efficacy and tolerability of CBD in patients with epilepsy at 16 epilepsy centers. Results: The study cohort comprised 311 patients with epilepsy with a median age of 11.3 (0‐72) years (235 children and adolescents, 76 adults). Therapy with CBD was off‐label in 91.3% of cases due to age, epilepsy subtype, lack of adjunct therapy with clobazam, and/or higher dose applied. CBD titration regimens were slower than recommended, with good tolerability of higher doses particularly in children. Of all patients, 36.9% experienced a reduction in seizure frequency of >50%, independent of their epilepsy subtype or clobazam co‐medication. The median observation period was 15.8 months. About one third of all patients discontinued therapy within the observation period due to adverse effects or lack of efficacy. Adverse effects were reported frequently (46.9%). Significance: Our study highlights that CBD has an antiseizure effect comparable to other antiseizure medications with a positive safety profile independent of the epilepsy subtype. Comedication with clobazam was not associated with a better outcome. Higher doses to achieve seizure frequency reduction were safe, particularly in children. These findings call for further trials for an extended approval of CBD for other epilepsy subtypes and for children <2 years of age. [ABSTRACT FROM AUTHOR]
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- 2023
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37. Current Knowledge and Prospects for Renal Hemangioblastoma and Renal Cell Carcinoma with Hemangioblastoma-like Features.
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Kojima, Fumiyoshi, Musangile, Fidele Y., Matsuzaki, Ibu, Yorita, Kenji, Kuroda, Naoto, Nagashima, Yoji, and Murata, Shin-ichi
- Subjects
CENTRAL nervous system - Abstract
Tumors exhibiting histopathological findings similar to those of hemangioblastoma of the central nervous system (CNS-HB) rarely develop in the kidneys. Currently, renal hemangioblastoma (RHB) is considered analogous to CNS-HB; however, they differ in gross appearance, as well as immunohistochemical and molecular findings. In contrast, some renal cell carcinomas reportedly comprise distinct, clear cell renal cell carcinoma (CCRCC)- and hemangioblastoma (HB)-like areas. Initially, renal cell carcinomas with HB-like features (RCC-HBs) were considered a morphological variant of CCRCC owing to their diverse histological findings. However, the immunohistochemical and molecular findings of RCC-HBs suggest that RCC-HB is distinct from CCRCC. Additionally, one of the RCC-HBs had a focal leiomyomatous stroma and TSC2 variant, suggesting that RCC-HB and RCC with fibromyomatous stroma (RCC-FMS) might belong to the same disease entity. Therefore, we comprehensively reviewed the clinical, pathological, and molecular features of RHB, RCC-HB, and the related tumors and discussed the similarities, differences, and relationships between them. We believe that our review would serve as a foundation for further investigation on elucidating the relationship between CNS-HB, RHB, RCC-HB, and RCC-FMS. [ABSTRACT FROM AUTHOR]
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- 2023
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38. Off-target activity of the 8 kb Dmp1-Cre results in the deletion of Tsc1 gene in mouse intestinal mesenchyme.
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Ghassib, Iya, Zhang, Honghao, Qi, Shuqun, Moshen, Rawan, Mishina, Yuji, Bellido, Teresita, and Liu, Fei
- Abstract
The Dmp1-Cre mouse, expressing Cre from an 8-kb DNA fragment of the mouse Dmp1 gene, is a common tool to study gene functions in osteocytes. Here we report that the deletion of Tsc1 (TSC complex subunit 1) by 8 kb Dmp1-Cre causes rectal prolapse in mice. Histological examination shows the presence of colon polyps in Tsc1-deficient mice in association with significantly larger colon and narrower lumen, which recapitulates the common polyps pathology in Tuberous Sclerosis, an autosomal dominant disorder caused by mutations in either TSC1 or TSC2. The intestine in Tsc1-deficient mice is also enlarged with the presence of taller villi. Using the Ai14 reporter mice that express a red fluorescence protein upon Cre recombination, we show that 8 kb Dmp1-Cre activity is evident in portion of the mesenchyme of the colon and small intestine. Lastly, our data show that Tsc1 deletion by Dmp1-Cre leads to an increased proliferation in the mesenchyme of colon, which at least partly contributes to the polyps pathology seen in this mouse model and is likely a contributing factor of the polyps in Tuberous Sclerosis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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39. EEG Spectral Features in Sleep of Autism Spectrum Disorders in Children with Tuberous Sclerosis Complex
- Author
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Cook, Ian A, Wilson, Andrew C, Peters, Jurriaan M, Goyal, Monisha N, Bebin, E Martina, Northrup, Hope, Krueger, Darcy, Leuchter, Andrew F, and Sahin, Mustafa
- Subjects
Education ,Health Sciences ,Psychology ,Rare Diseases ,Neurosciences ,Pediatric ,Prevention ,Intellectual and Developmental Disabilities (IDD) ,Tuberous Sclerosis ,Brain Disorders ,Clinical Research ,Autism ,Sleep Research ,Mental Health ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Mental health ,Autism Spectrum Disorder ,Brain Waves ,Child ,Child ,Preschool ,Female ,Humans ,Male ,Sleep ,TSC ,EEG ,Biomarkers ,TACERN Study Group ,Psychology and Cognitive Sciences ,Developmental & Child Psychology ,Health sciences - Abstract
Tuberous sclerosis complex (TSC) is a multisystem disorder with increased prevalence of autism spectrum disorders (ASDs). This project aimed to characterize the autism phenotype of TSC and identify biomarkers of risk for ASD. Because abnormalities of EEG during sleep are tied to neurodevelopment in children, we compared electroencephalographic (EEG) measures during Stage II sleep in TSC children who either did (ASD+) or did not (ASD-) exhibit symptoms of ASD over 36-month follow up. Relative alpha band power was significantly elevated in the ASD+ group at 24 months of age with smaller differences at younger ages, suggesting this may arise from differences in brain development. These findings suggest that EEG features could enhance the detection of risk for ASD.
- Published
- 2020
40. Epidemiology and disease burden of tuberous sclerosis complex in France: A population‐based study based on national health insurance data
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Francis Fagnani, Caroline Laurendeau, Marie deZelicourt, and Jade Marshall
- Subjects
healthcare cost ,healthcare resource utilization ,prevalence ,refractory epilepsy ,TSC ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective Tuberous sclerosis complex (TSC) is a rare multisystem disorder, often associated with epilepsy. This retrospective study aimed to identify patients with TSC, including those with epilepsy, from a French healthcare claims database, and to report incidence, prevalence, and healthcare costs and resource utilization. Methods The anonymized French health insurance database (SNDS) covers almost the entire French population. Patients with TSC were identified as having ≥1 International Classification of Diseases, Tenth Revision (ICD‐10) diagnosis code Q85.1 or a long‐term disease (LTD) registration over the inclusion period (2006–2017). Patients with an ICD‐10 epilepsy code or who were dispensed ≥1 antiseizure medication (ASM) in the same year or after their TSC diagnosis were identified as having TSC with epilepsy. Newly diagnosed patients over the inclusion period constituted the incident cohort. Healthcare costs (patients with recorded costs only), healthcare resource use, and ASM dispensation are reported for patients with 2018 data. Results In 2018, 3139 prevalent patients with TSC were identified (crude prevalence, 4.69 per 100 000); the incident cohort comprised 2988 patients (crude incidence, 0.44 per 100 000). Among patients with TSC, 67% (2101/3139) had epilepsy (mean [standard deviation, SD] age: 28.8 [18.8] years; male: 48%). Among patients with epilepsy, total mean (SD) annual healthcare costs were €11 413 (27 620) per capita (outpatient, 63%; inpatient, 37%), 46% were hospitalized during 2018 (mean [SD]: 1.8 [10.9] acute care visits per patient), and 65% visited a hospital specialist. Among patients with epilepsy, medication (mean [SD]: €4518 [12 102] per capita) was the greatest contributor (63%) to outpatient costs, and in 2018, 74% were dispensed ≥1 different ASM and 9% were dispensed ≥4 ASMs. Significance TSC with epilepsy was associated with substantial healthcare costs and resource utilization, particularly outpatient and medication costs. Many patients with TSC with epilepsy were prescribed multiple ASMs, suggesting refractory epilepsy.
- Published
- 2022
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41. Hereditary Renal Cell Carcinoma Syndromes
- Author
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Jodie K. Maranchie, Brian M. Schuch, Gennady Bratslavsky, and Eamonn R. Maher
- Subjects
renal cancer ,familial ,genetics ,syndrome ,vhl ,hlrcc ,bhd ,tsc ,shd ,bap1 ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
A number of germline syndromes that predispose affected individuals to develop renal cancer have been described, each with unique manifestations, histopathology, and tumor behavior. Patients tend to present with early onset and/or multifocal tumors. Familiarity with these syndromes helps to identify at-risk patients and recommend genetic screening. Early detection is essential to direct appropriate cancer surveillance protocols for patients and other family members and care strategies that preserve lifelong renal function while minimizing risk of death from metastatic cancer.
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- 2022
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42. Lymphangioleiomyomatosis: a metastatic lung disease.
- Author
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Kundu, Nandini and Holz, Marina K.
- Subjects
- *
LUNG diseases , *SOMATIC mutation , *LUNGS , *METASTASIS , *CELL populations , *CELL communication - Abstract
Lymphangioleiomyomatosis (LAM) is a rare disease affecting women, caused by somatic mutations in the TSC1 or TSC2 genes, and driven by estrogen. Similar to many cancers, it is metastatic, primarily to the lung. Despite its monogenetic nature, like many cancers, LAM is a heterogeneous disease. The cellular constituents of LAM are very diverse, including mesenchymal, epithelial, endothelial, and immune cells. LAM is characterized by dysregulation of many cell signaling pathways, distinct populations of LAM cells, and a rich microenvironment, in which the immune system appears to play an important role. This review delineates the heterogeneity of LAM and focuses on the metastatic features of LAM, the deregulated signaling mechanisms and the tumor microenvironment. Understanding the tumor-host interaction in LAM may provide insights into the development of new therapeutic strategies, which could be combinatorial or superlative to Sirolimus, the current U.S. Food and Drug Administration-approved treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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43. Association of multiple retinal nodular hamartomas and "confetti" skin lesions with end-stage renal disease in patients with tuberous sclerosis.
- Author
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Prelevic, Vladimir, Juric, Ivana, Bevc, Sebastijan, Marcun-Varda, Natasa, Aleckovic-Halilovic, Mirna, Mesic, Enisa, Bilic, Hrvoje, Grujicic, Milorad, Zabic, Igor, Josipovic, Josipa, Vujicic, Bozidar, Marinaki, Smaragdi, Simic-Ogrizovic, Sanja, Milinkovic, Marija, Azasevac, Tijana, Idrizi, Alma, Arnol, Miha, Radunovic, Danilo, Antunovic, Tanja, and Jukic, Nikolina Basic-
- Abstract
Purpose: The main purpose of this study is to explore characteristics of patients with chronic kidney disease in tuberous sclerosis (TSC) and to underline differences in clinical characteristics between end-stage renal disease (ESRD) patients and patients in earlier stages of chronic kidney disease. Methods: This multicentric, retrospective study included data for 48 patients from seven South-Eastern European countries (Albania, Bosnia and Herzegovina, Croatia, Greece, Montenegro, Serbia, Slovenia) in the period from February to August 2020. Researchers collected data from local and national nephrological and neurological registries and offered clinical and laboratory results from medical histories in follow-up periods. Results: This study enrolled 48 patients with a median age of 32.3 years (range, 18–46 years), and predominant female gender (60.45%). The percentage of patients with chronic kidney disease (CKD) diagnosis of the total number of patients was 66.90%, with end-stage renal disease development in 39.6%. The most prevalent renal lesions leading to chronic kidney disease were angiomyolipomas (AMLs) in 76.6%, while multiple renal cysts were present in 42.6% of patients. Nephrectomy was performed in 43% of patients, while the mTOR inhibitors were used in 18 patients (37.5%). The majority of patients had cutaneous manifestations of tuberous sclerosis—83.30% had hypomelanotic cutaneous lesions, and 68.80% had angiofibromas. Multiple retinal nodular hamartomas and "confetti" skin lesions were more frequent in end-stage renal disease (ESRD) than in patients with earlier stages of chronic kidney disease (p-0.033 and 0.03, respectively). Conclusion: Our study has also shown that retinal hamartomas and "confetti" skin lesions are more frequent in end-stage renal diseases (ESRD) patients than in other chronic kidney disease (CKD) patients. Usage of mTOR inhibitors can also reduce the number of complications and associated with tuberous sclerosis, such as dermatological manifestations and retinal hamartoma, which are more common in the terminal stage of chronic kidney disease. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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44. Case report: Responses to the combination of gemcitabine with sirolimus in two patients with TSC-mutated sarcomas
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Elise F. Nassif, Cissimol P. Joseph, Rossana Lazcano, Jocelyn T. Joseph, Prapassorn Thirasastr, Alexander J. Lazar, and Neeta Somaiah
- Subjects
sarcoma ,TSC ,mTOR - mammalian target of rapamycin ,gemcitabine ,PEComa ,nab-sirolimus ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
TSC-mutated sarcomas are rare molecular and histologic types of sarcoma. Due to the presence of their specific oncogenic driver mutation, these sarcomas are particularly sensitive to mTOR inhibitors. Recently, nab-sirolimus, an albumin-bound mTOR inhibitor, was approved by the Food and Drug Administration (FDA) for PEComas, which harbor a TSC mutation, and this drug remains the only FDA-approved systemic treatment for these tumors. We report on two cases of patients with TSC-mutated sarcomas who experienced significant responses to the combination of gemcitabine and sirolimus, after progression on prior gemcitabine-based chemotherapy and single agent mTOR inhibition with nab-sirolimus. Preclinical and clinical data support rationale for a synergistic effect of the combination. This combination may represent a valid therapeutic option after failure of nab-sirolimus in these patients, with no standard-of-care treatment options.
- Published
- 2023
- Full Text
- View/download PDF
45. Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient Cells.
- Author
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Champion, Jesse D., Dodd, Kayleigh M., Lam, Hilaire C., Alzahrani, Mohammad A. M., Seifan, Sara, Rad, Ellie, Scourfield, David Oliver, Fishel, Melissa L., Calver, Brian L., Ager, Ann, Henske, Elizabeth P., Davies, David Mark, Kelley, Mark R., and Tee, Andrew R.
- Subjects
- *
IN vitro studies , *CELL culture , *WESTERN immunoblotting , *OXIDATION-reduction reaction , *HYPOXEMIA , *TUBEROUS sclerosis , *PHOSPHORYLATION - Abstract
Simple Summary: Tuberous sclerosis complex (TSC) is a genetic disease where patients are predisposed to tumors and neurological complications. Current therapies for this disease are not fully curative. We aimed to explore novel drug targets and therapies that could further benefit TSC patients. This work uncovered a novel pathway that drives disease in TSC cell models involving redox factor-1 (Ref-1). Ref-1 is a protein that turns on several key transcription factors that collectively promote tumor growth and survival through direct redox signaling. Processes regulated by Ref-1 include angiogenesis, inflammation, and metabolic transformation. Therefore, this work reveals a new drug target, where inhibitors of Ref-1 could have an additional benefit compared to current drug therapies. Therapies with the mechanistic target of rapamycin complex 1 (mTORC1) inhibitors are not fully curative for tuberous sclerosis complex (TSC) patients. Here, we propose that some mTORC1-independent disease facets of TSC involve signaling through redox factor-1 (Ref-1). Ref-1 possesses a redox signaling activity that stimulates the transcriptional activity of STAT3, NF-kB, and HIF-1α, which are involved in inflammation, proliferation, angiogenesis, and hypoxia, respectively. Here, we demonstrate that redox signaling through Ref-1 contributes to metabolic transformation and tumor growth in TSC cell model systems. In TSC2-deficient cells, the clinically viable Ref-1 inhibitor APX3330 was effective at blocking the hyperactivity of STAT3, NF-kB, and HIF-1α. While Ref-1 inhibitors do not inhibit mTORC1, they potently block cell invasion and vasculature mimicry. Of interest, we show that cell invasion and vasculature mimicry linked to Ref-1 redox signaling are not blocked by mTORC1 inhibitors. Metabolic profiling revealed that Ref-1 inhibitors alter metabolites associated with the glutathione antioxidant pathway as well as metabolites that are heavily dysregulated in TSC2-deficient cells involved in redox homeostasis. Therefore, this work presents Ref-1 and associated redox-regulated transcription factors such as STAT3, NF-kB, and HIF-1α as potential therapeutic targets to treat TSC, where targeting these components would likely have additional benefits compared to using mTORC1 inhibitors alone. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
46. Construction of TSC2 knockout cell line using CRISPR/Cas9 system and demonstration of its effects on NIH-3T3 cells.
- Author
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Wang, Xu, Zhao, Yang, Wang, Zhan, Liao, Zhangcheng, and Zhang, Yushi
- Abstract
Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder involving multiple organ systems. TSC2 gene plays an important role in the development of TSC. The most common kidney manifestation of TSC is renal angiomyolipoma (RAML). TSC-RAML is more likely to be bilateral multiple tumors and tends to destroy the renal structure and damages renal function severely. As a result, patients with TSC-RAML often miss the opportunity for surgical treatment when TSC-RAML is diagnosed, causing difficulty in obtaining tumor specimens through surgery. Due to this difficulty, model cell lines must be constructed for scientific research. In this paper, TSC2 was knocked out in NIH-3T3 cell lines by CRISPR/Cas9 system. PCR, WB and mTOR inhibitor drug sensitivity test showed that the TSC2 knockout NIH-3T3 cells were successfully constructed. The ability of proliferation and invasion in TSC2 KO NIH-3T3 cells were higher than those in wild type group. The constructed KO cell line lay the foundation for further study of TSC. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
47. Epidemiology and disease burden of tuberous sclerosis complex in France: A population‐based study based on national health insurance data.
- Author
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Fagnani, Francis, Laurendeau, Caroline, de Zelicourt, Marie, and Marshall, Jade
- Subjects
TUBEROUS sclerosis ,NATIONAL health insurance ,MEDICAL care cost statistics ,PEOPLE with epilepsy ,FRENCH people ,MEDICAL care costs - Abstract
Objective: Tuberous sclerosis complex (TSC) is a rare multisystem disorder, often associated with epilepsy. This retrospective study aimed to identify patients with TSC, including those with epilepsy, from a French healthcare claims database, and to report incidence, prevalence, and healthcare costs and resource utilization. Methods: The anonymized French health insurance database (SNDS) covers almost the entire French population. Patients with TSC were identified as having ≥1 International Classification of Diseases, Tenth Revision (ICD‐10) diagnosis code Q85.1 or a long‐term disease (LTD) registration over the inclusion period (2006–2017). Patients with an ICD‐10 epilepsy code or who were dispensed ≥1 antiseizure medication (ASM) in the same year or after their TSC diagnosis were identified as having TSC with epilepsy. Newly diagnosed patients over the inclusion period constituted the incident cohort. Healthcare costs (patients with recorded costs only), healthcare resource use, and ASM dispensation are reported for patients with 2018 data. Results: In 2018, 3139 prevalent patients with TSC were identified (crude prevalence, 4.69 per 100 000); the incident cohort comprised 2988 patients (crude incidence, 0.44 per 100 000). Among patients with TSC, 67% (2101/3139) had epilepsy (mean [standard deviation, SD] age: 28.8 [18.8] years; male: 48%). Among patients with epilepsy, total mean (SD) annual healthcare costs were €11 413 (27 620) per capita (outpatient, 63%; inpatient, 37%), 46% were hospitalized during 2018 (mean [SD]: 1.8 [10.9] acute care visits per patient), and 65% visited a hospital specialist. Among patients with epilepsy, medication (mean [SD]: €4518 [12 102] per capita) was the greatest contributor (63%) to outpatient costs, and in 2018, 74% were dispensed ≥1 different ASM and 9% were dispensed ≥4 ASMs. Significance: TSC with epilepsy was associated with substantial healthcare costs and resource utilization, particularly outpatient and medication costs. Many patients with TSC with epilepsy were prescribed multiple ASMs, suggesting refractory epilepsy. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
48. Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex.
- Author
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Bongaarts, Anika, Mijnsbergen, Caroline, Anink, Jasper J., Jansen, Floor E., Spliet, Wim G. M., den Dunnen, Wilfred F. A., Coras, Roland, Blümcke, Ingmar, Paulus, Werner, Gruber, Victoria E., Scholl, Theresa, Hainfellner, Johannes A., Feucht, Martha, Kotulska, Katarzyna, Jozwiak, Sergiusz, Grajkowska, Wieslawa, Buccoliero, Anna Maria, Caporalini, Chiara, Giordano, Flavio, and Genitori, Lorenzo
- Subjects
- *
TUBEROUS sclerosis , *DNA methylation , *ASTROCYTOMAS , *BRAIN tumors , *GENE expression - Abstract
Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
49. Saving Water and Operating Costs at NREL's HPC Data Center
- Author
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Sickinger, David
- Published
- 2017
50. The TSC1‐mTOR‐PLK axis regulates the homeostatic switch from Schwann cell proliferation to myelination in a stage‐specific manner
- Author
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Jiang, Minqing, Rao, Rohit, Wang, Jincheng, Wang, Jiajia, Xu, Lingli, Wu, Lai Man, Chan, Jonah R, Wang, Huimin, and Lu, Q Richard
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Rare Diseases ,Tuberous Sclerosis ,Brain Disorders ,1.1 Normal biological development and functioning ,Underpinning research ,Animals ,Cell Cycle ,Cell Cycle Proteins ,Cell Proliferation ,Female ,Homeostasis ,Male ,Mice ,129 Strain ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Neural Stem Cells ,Protein Kinase Inhibitors ,Protein Serine-Threonine Kinases ,Proto-Oncogene Proteins ,Pteridines ,Schwann Cells ,Sciatic Nerve ,TOR Serine-Threonine Kinases ,Transcriptome ,Tuberous Sclerosis Complex 1 Protein ,mTOR signaling ,myelination ,polo-like kinase ,proliferation ,Schwann cell ,TSC ,tumor suppressor ,Neurology & Neurosurgery - Abstract
Proper peripheral myelination depends upon the balance between Schwann cell proliferation and differentiation programs. The serine/threonine kinase mTOR integrates various environmental cues to serve as a central regulator of cell growth, metabolism, and function. We report here that tuberous sclerosis complex 1 (TSC1), a negative regulator of mTOR activity, establishes a stage-dependent program for Schwann cell lineage progression and myelination by controlling cell proliferation and myelin homeostasis. Tsc1 ablation in Schwann cell progenitors in mice resulted in activation of mTOR signaling, and caused over-proliferation of Schwann cells and blocked their differentiation, leading to hypomyelination. Transcriptome profiling analysis revealed that mTOR activation in Tsc1 mutants resulted in upregulation of a polo-like kinase (PLK)-dependent pathway and cell cycle regulators. Attenuation of mTOR or pharmacological inhibition of polo-like kinases partially rescued hypomyelination caused by Tsc1 loss in the developing peripheral nerves. In contrast, deletion of Tsc1 in mature Schwann cells led to redundant and overgrown myelin sheaths in adult mice. Together, our findings indicate stage-specific functions for the TSC1-mTOR-PLK signaling axis in controlling the transition from proliferation to differentiation and myelin homeostasis during Schwann cell development.
- Published
- 2018
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