26 results on '"TSC"'
Search Results
2. Regulating Together in Tuberous Sclerosis Complex (RT)
- Author
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United States Department of Defense
- Published
- 2024
3. HtrA4 is well conserved only in higher primates and functionally important for EVT differentiation.
- Author
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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. 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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5. 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
- Abstract
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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6. 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
- Abstract
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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7. Prevalence of Liver Steatosis in Tuberous Sclerosis Complex Patients: A Retrospective Cross-Sectional Study.
- Author
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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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8. 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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9. 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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10. 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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11. 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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12. 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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13. 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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14. 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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15. 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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16. Prevalence of Liver Steatosis in Tuberous Sclerosis Complex Patients: A Retrospective Cross-Sectional Study
- Author
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Thaïs De Bock, Carola Brussaard, Silke François, Karlien François, Laura Seynaeve, Anna Jansen, Karl Martin Wissing, and Peter Janssens
- Subjects
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.
- Published
- 2024
- Full Text
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17. Atypical noncontiguous TSC2/PKD1 gene deletions presenting as tuberous sclerosis/polycystic kidney disease contiguous gene syndrome.
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Ventayol-Guirado M, Torres L, Asensio-Landa V, Pérez-Granero Á, Madrid MI, Hernandez-Rodriguez J, Llull-Alberti MV, Lumbreras J, Escribà S, Pons M, Roldan J, Martínez-López I, Heine-Suñer D, and Santos-Simarro F
- Abstract
Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct disorders typically associated with pathogenic variants in TSC1 and TSC2 for the former and PKD1 and PKD2 for the latter. TSC2 and PKD1 lie adjacent to each other, and large deletions comprising both genes lead to TSC2/PKD1 contiguous gene deletion syndrome (CGS). In this study, we describe a young female patient exhibiting symptoms of TSC2/PKD1 CGS in which genetic analysis disclosed two noncontiguous partial gene deletions in TSC2 and PKD1 that putatively are responsible for the manifestations of the syndrome. Further analysis revealed that both deletions appear to be de novo on the maternal chromosome, presumably with a germline origin. Despite extensive analysis, no maternal chromosomal rearrangement triggering these pathogenic variants was detected. This case elucidates a unique pathogenesis for TSC2/PKD1 CGS, diverging from the common contiguous deletions typically observed, marking the first reported instance of TSC2/PKD1 CGS caused by independent, functionally significant partial gene deletions., (© 2024 Wiley Periodicals LLC.)
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- 2024
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18. Case Report: Patent ductus arteriosus with tuberous sclerosis complex.
- Author
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Chen T, Wu X, and Wang Y
- 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Chen, Wu and Wang.)
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- 2024
- Full Text
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19. The Spectrum of "TFEopathies" - Flipping the mTOR Switch in Renal Tumorigenesis.
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Alesi N, Asrani K, Lotan TL, and Henske EP
- Abstract
The Mammalian Target of Rapamycin Complex 1 (mTORC1) is a serine threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However recent studies have indicated that mTORC1 may be active towards its canonical substrates, 4EBP1 and S6K, involved in mRNA translation and protein synthesis, and inactive towards TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt Hogg Dube (BHD) and recently, Tuberous Sclerosis Complex (TSC). Furthermore, TFEB and TFE3 hyperactivation in these syndromes, and in translocation Renal Cell Carcinomas (tRCC), drives mTORC1 activity towards the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity towards 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies". Currently, there no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research.
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- 2024
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20. Loss of Tuberous Sclerosis Complex 2 confers inflammation via dysregulation of Nuclear factor kappa-light-chain-enhancer of activated B cells.
- Author
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McPhail DK, Alzahrani MAM, Martin KR, Calver BL, Harwood AJ, MacKeigan JP, Davies DM, and Tee AR
- Abstract
Background: Aberrant activation of mTORC1 is clearly defined in TSC, causing uncontrolled cell growth. While mTORC1 inhibitors show efficacy to stabilise tumour growth in TSC, they are not fully curative. Disease facets of TSC that are not restored with mTOR inhibitors might involve NF-κB. The study aimed to characterise NF-κB in the context of TSC., Results: Enrichment of NF-κB-regulated genes was observed in TSC patient tumours, SEN/SEGAs, cortical tubers and a TSC tumour-derived cell line (621 - 101). Highlighting an inflammatory component of TSC, TSC cell models showed an elevated level of NF-κB and STAT3 activation. Herein, we report a dysregulated inflammatory phenotype of TSC2 -deficient cells where NF-κB promotes autocrine signalling involving IL-6. Of importance, mTORC1 inhibition does not block this inflammatory signal to promote STAT3, while NF-κB inhibition was much more effective. Combined mTORC1 and NF-κB inhibition was potent at preventing anchorage-independent growth of TSC2 -deficient cells, and unlike mTORC1 inhibition alone was sufficient to prevent colony regrowth after cessation of treatment., Conclusion: This study reveals autocrine signalling crosstalk between NF-κB and STAT3 in TSC cell models. Furthermore, the data presented indicate that NF-κB pathway inhibitors could be a viable adjunct therapy with the current mTOR inhibitors to treat TSC., Competing Interests: Declarations Competing interests The authors declare that they have no competing interests. While this study is funded in part by Health and Care Research Wales, the views expressed are those of the authors and not necessarily those of Health and Care Research Wales or the Welsh Government.
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- 2024
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21. TSC1 splicing mutation in renal angiomyolipoma with epithelial cysts without fat: A very rare case report and literature review.
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Xu Q, Yin L, Tao J, and Peng F
- 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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)
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- 2024
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22. Loss of Tsc2 Results in Abnormal Postnatal Neurogenesis and Striatal Hamartomas
- Author
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Riley, Victoria
- Subjects
- TSC, SEGA, tsc2, mTOR, hamartoma, translation, Developmental Neuroscience, Neuroscience and Neurobiology
- Abstract
Billions of years of evolution have culminated in the most complex organ in all of biology: the brain. Its capacity to sense, store, and predict information uniquely bestows humans with the capability to generate art, music, language, and math and sets humans apart from other species. It is therefore prudent and worthwhile to study the brain and its development. A critical aspect of brain development is neurogenesis, or the production of neurons. Neurogenesis is facilitated by neural stem cells (NSCs) and is influenced by the mTORC1 signaling pathway. For NSCs to differentiate and become committed to a neuronal cell fate, mTORC1 signaling must decrease in amplitude. This is likely due to the role that mTORC1 signaling plays in regulating mRNA translation which are tightly controlled in NSCs. Hyperactive mTORC1 signaling can result from the inactivation of either the Tsc1 or Tsc2 gene and is considered the main driver of symptoms in the developmental disorder Tuberous Sclerosis Complex (TSC). TSC is characterized by congenital growths that form in multiple organ systems, including the brain. In TSC, the brain has cellular abnormalities leading to three types of lesions: cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs). TSC lesions are associated with neuropsychiatric symptoms including epilepsy, autism spectrum disorders, intellectual delay, and behavioral abnormalities. Given the role that mTORC1 signaling plays in NSC differentiation, NSCs were examined in a Tsc2 null mouse model. Briefly, genetic recombination was used to inactivate the Tsc2 gene in NSCs of the ventricular-subventricular zone. Tsc2 removal altered aspects of transcription and translation, including translational efficiency. Loss of Tsc2 caused striatal growths reminiscent of SEGAs. The growths contained NSCs and differentiated progeny including neurons and glia, possibly indicating abnormal neurogenesis due to Tsc2 loss in NSCs. There is evidence that Tsc2 loss, subsequent upregulation of mTORC1 signaling, and translational dysregulation cause NSCs to retain aspects of stemness, which could potentially contribute to TSC growth formation.
- Published
- 2024
23. Investigation of high resistivity [formula omitted]-type FZ silicon diodes after 60Co [formula omitted]-irradiation.
- Author
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Liao, C., Fretwurst, E., Garutti, E., Schwandt, J., Pintilie, I., Nitescu, A., Himmerlich, A., Moll, M., Gurimskaya, Y., and Li, Z.
- Subjects
- *
SILICON diodes , *DEEP level transient spectroscopy , *IRRADIATION , *BORON , *BASE isolation system - Abstract
In this work, the effects of 60Co γ -ray irradiation on high resistivity p -type diodes have been investigated. The diodes were exposed to dose values of 0.1, 0.2, 1, and 2 MGy. Both macroscopic (I – V , C – V) and microscopic investigations, by means of Thermally Stimulated Current (TSC) and Deep Level Transient Spectroscopy (DLTS) techniques, were conducted to characterize the radiation-induced changes. The investigated diodes were manufactured on high resistivity p -type Float Zone (FZ) silicon and were further classified into two types based on the isolation technique between the pad and guard ring: p -stop and p -spray. After irradiation, the macroscopic results of current–voltage and capacitance–voltage measurements were obtained and compared with existing literature data. Additionally, the microscopic measurements focused on the development of the concentration of different radiation-induced defects, including the Boron interstitial-Oxygen interstitial (B i O i) complex, the Carbon interstitial-Oxygen interstitial (C i O i) defect, the H40K, and the so-called I P ∗. To investigate the thermal stability of induced defects in the bulk, isochronal annealing studies were performed in the temperature range of 100 °C to 300 °C. These annealing processes were carried out on diodes irradiated with doses of 1 and 2 MGy. Furthermore, in order to investigate the unexpected results observed in the C – V measurements after irradiation with high dose values, the surface conductance between the pad and guard ring was measured as a function of both dose and annealing temperature. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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24. Challenges of siblings with tuberous sclerosis showing various manifestations and severe complications.
- Author
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Purbasari U, Prihartono NA, Helda N, Audita FR, and Dharmawan BS
- 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., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)
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- 2024
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25. A 28-year-old patient with tuberous sclerosis associated with renal angiomyolipoma:A rare case report and literature review.
- Author
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Haydar H, Sleiay M, Alqreea M, Almohamed A, Alrajab D, Alsaleh M, and Lutfi MY
- 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., Competing Interests: No conflict of interest., (© 2024 The Authors.)
- Published
- 2024
- Full Text
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26. Soft Tissue Perivascular Epithelioid Cell Tumors.
- Author
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Hammer PM and Tan SY
- Subjects
- Humans, Biomarkers, Tumor genetics, Perivascular Epithelioid Cell Neoplasms diagnosis, Perivascular Epithelioid Cell Neoplasms genetics, Perivascular Epithelioid Cell Neoplasms pathology, Neoplasms, Connective and Soft Tissue
- Abstract
Perivascular epithelioid cell tumors (PEComas) are a heterogenous group of mesenchymal neoplasms with a mixed myomelanocytic immunophenotype. PEComa-family tumors include angiomyolipoma, lymphangioleiomyomatosis, and a large category of rare neoplasms throughout the body that are now classified under the umbrella term "PEComa." This review focuses on recent advances in the clinicopathological and molecular features of PEComas, with an emphasis on PEComas that originate in soft tissue., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
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